Today, I'll be talking about transplant metrics for liver transplantation, and I'll review an overview of transplant metrics with particular focus on transplant center metrics, and then I'll talk about proposed changes that are under public review or transplant center metrics. If these are approved, which could occur within this calendar year, this will change how your center is adjudicated in terms of its transplant center performance. And then to conclude, I'll talk about upcoming changes that have been approved, and we'll start for organ procurement organization metrics, and these will likely have an important impact on liver organ procurement and volumes. So liver transplant metrics, these are designed to measure safe, effective, and high-quality care, and hopefully in doing so, this would promote excellent or high-quality care. However, the best approach or whether this approach is effective is unknown, and it's unknown in terms of what the best transplant center metrics are. And when we talk about liver transplant center metrics, it's important to remember that there are many stakeholders, including patients, providers, organ procurement organizations, and increasingly insurance and regulatory agencies. And in fact, many insurance companies utilize transplant center metrics in making decisions about where to refer patients, and these have important implications for transplant center volumes and revenue. Transplant center metrics can be divided into the different phases of care, and I would highlight this because the new transplant center metrics under review for UNOS have used these similar divisions in terms of how to measure transplant center performance. And these include referral and waitlisting performance of the center. This has a lot to do with how hepatologists care for patients and the selection of patients who are waitlisted, the inpatient transplant surgery admission, evaluates the center's performance in terms of technical surgical abilities, and then short-term follow-up, which is usually the first one to three months after the post-transplant discharge, measures how well the center manages surgical complications, and then longer-term follow-up is all the care thereafter, which is mainly focused on management of medical complications. And then there are, of course, important program metrics to look at. Aside from an academic endeavor, it's important to remember that transplant center metrics have important implications for the center. OPTN has an obligation as part of its charge from HHS to measure transplant center performance to ensure competency at the transplant center and to ensure patient safety. And the member and professional standards committee of UNOS has the authority of the OPTN to develop transplant center metrics and to enforce centers that are underperforming related to these metrics. The current metric by which transplant centers are adjudicated is the one-year patient and graft survival, and these rates are created by the Scientific Registry for Transplant Recipients, SRTR, in terms of risk-adjusted outcome models developed by SRTR. And the results of these are available on biannual publicly reported PSRs or program-specific reports that can be found on SRTR.org. And in addition to results of one-year patient and graft survival, data from waitlist outcomes, organ acceptance ratios, and transplant rates can also be found, as well as a plethora of other data, including demographics of the transplant waiting list and transplant recipients. And all of this information is intended to capture transplant quality, but over time, there's been concern expressed that these metrics may not be as relevant or useful as some of the proposed metrics that I'll describe in just a minute. One of the problems with transplant metrics is that the past doesn't necessarily predict the future. If an insurance company is evaluating outcomes at a transplant center, the one-year patient and graft survival rates may be developed from patients who are transplanted as far back as three years ago. And when a patient's coming to a center currently, their transplant may not occur for an additional two or three years. So decisions for patients today who may not be transplanted for two or three years, based on information that was developed two or three years in the past, may not be relevant for that patient because the past performance, especially when it's separated by so much time, may not predict the future for the particular patient who's presenting today. And as I'll show you, transplant centers can adjust their practice to maximize metrics. It's also important to remember that the inter-center difference, the difference between transplant centers is relatively small. A poorly performing transplant center may have a one-year patient survival rate of 89%, whereas a highly performing center may have a one-year patient survival rate of 92%. Whether that 3% difference is clinically relevant to change selection criteria for an insurance company or a particular patient and how they select a transplant center is really not clear. And perhaps most important, the current metric of patient graft survival only evaluates one aspect of care and one aspect of performance of the transplant center. It doesn't really reflect the patient experience because from a patient standpoint, they want to know how well do I do from the time that I appear at the center or from the time that I'm listed at the center. And the current patient graft survival rates do not evaluate this pre-transplant aspect of patient care. And it's been also been noted that organ acceptance rates vary across the country. Centers can adjust their practice to maximize metrics. And certain centers have been noted to accept only the best organs to maximize their one-year patient graft survival rates, whereas their waiting list mortality rates may be very high. And organ acceptance rates, therefore, vary widely across the country and there's been a movement to try and push centers to accept poor quality organs that may function well. So I'll now show you the proposed changes for transplant center metrics. And again, this proposal is out for public comment or public comment may have just closed. And this is, again, something that can change how your transplant center is measured in terms of its performance. And the proposals to change the current metric from one-year patient graft survival to a combined metric shown here, which would evaluate four different phases of care, including organ acceptance rate, wait list survival, 30-day graft survival, and 360-day graft survival. As I pointed out earlier, organ acceptance rates as a metric is important because it would likely enforce good medical practice. It would likely force centers to use good but non-perfect organs. If they were able to make these choices wisely, they could reduce their waiting list mortality rates while maintaining excellent post-transplant outcomes. Wait list survival is a metric, as I pointed out, better reflects the patient experience, how they do before the transplant. It would measure the chronic disease management at the center, which is largely the responsibility of hepatology. It would have a lot to do with patient selection and management. And again, organ selection would also be important in this metric as well. The final parts of the combined metric include 90-day and 365-day graft survival rates. Why were these divided into these two times, 90 days and 365 days as a metric? It was thought by the NPSC that this 90-day metric would measure patient selection and the management of immediate post-operative surgical complications, and that the 365-day metric would measure something different, which would largely be longer-term management, longer-term immunosuppression complications, and the management of medical complications during this longer phase of follow-up. Graft survival, again, is the only metric and not patient survival. It's likely a more sensitive metric because patients can lose the graft and still survive, whereas patient survival is not as sensitive a metric as graft survival in that respect. It's also simpler, and it was thought to capture the important safety issues relative to transplant center performance. I'll just briefly touch on performance cutoffs and centers that exceed performance cutoffs with a weightless mortality rate with a hazard ratio over 1.75, an organ acceptance rate of less than 0.3, and 90-day and 365-day graft survival hazard ratios over 1.75 would be at risk for an NPSC inquiry. A yellow zone or patients trending in the wrong direction would be notified, and an offer of assistance for that center would be provided if the center so wished. Patients who are in the red zone and exceeded these cutoffs would be at risk for an NPSC inquiry. Now, these transplant center metrics, again, are under public comment review, or this may have just closed, and if approved, as they will go to the UNOS Board in December of this year, these could be out and impacting your transplant center assessment with the first cohort being presented in July of 2022, which would be July of next year. And now I'd like to review some of the upcoming changes for the organ procurement organization metrics, as these will likely have important or cause important changes in the procurement of organs and hopefully increase the number of organs transplanted over the upcoming years. The good news about organ procurement organization metrics is that for the past 10 years, the number of liver transplants that have been performed has increased from just over 6,000 in 2012 to a 50% increase that is anticipated to be over 9,000 by the end of this year. So by this measure, OPOs are performing well, and liver transplant across the United States is increasing every year over the past 10 years. But there have been, as I've noted, some concerns have been expressed in the lay press as well as the academic press. On the top left is an article by Ted Alcorn in the New York Times that says New York has world-class hospitals, but why is it so bad for people in need of transplants? New York has the lowest rate of organ donation registration in the country, thousands languish on wait lists, and hundreds die needlessly every year. And they go on to point out that New York has the poorest performing OPO in the United States, pointing out the wide variation in performance across the country within OPOs. And on the bottom right of the slide is a headline from a recent HAT showing that pressure is building on OPO oversights and highlighting that CMS has recently finalized an OPO reform rule that will be enforced in the upcoming year to improve OPO oversight and hopefully performance. And I'll review this in the final minutes of my talk here. It's important to remember that an OPO is an organ procurement organization, and the OPO covers a donor service area, which is a geographic area. So the DSA is a donor service area, the geographic area covered by the OPO. This is important because there's a proposal, as I'll show you, that will be in effect in upcoming years where OPOs could lose their coverage of the DSA and poorly performing OPOs could be overtaken in terms of they could lose their donor service area to a higher performing OPO in a nearby DSA. So in terms of OPOs, there's 58 in the United States, and critics have pointed out that these OPOs have no local competition as compared to transplant centers. As I previously noted, there's been variable performance within these OPOs across the country, and this has led to concerns about their efficiency and effectiveness, and this has now been translated into political pressure to change performance metrics that, again, have been passed by CMS and will go into effect next year, and I'll describe those here shortly. The three major changes in my review of this are shown here, the first of which is the definition of a potential donor. The current definition is a, quote, eligible donor, end quote, and this is a self-reported metric, and it's thought to be relatively inaccurate because it's been noted that a fraction of patients who went on to donate were actually not included in the eligible donor metric, and so there's a movement, and in fact, the new metric will broaden the definition of a potential donor for a more accurate representation of actual potential donors, and using a more objective measure, primarily with the use of diagnosis codes through electronic medical records so that the definition of a potential donor will be broadened and hopefully more objective. The second change is that the metric of organs transplanted will be used instead of not just organs donated, and in doing so, it's hoped that the organ procurement organizations will go after donors who may only donate one organ, and more interestingly, as I'll show you, OPO recertification will be at risk based on their performance according to these metrics. In particular, the current metric of donor conversion rate, which is the current metric, is the number of donors who donate at least one organ expressed as a percentage of eligible deaths will change to the new metric of donation rate, which is the number of donors who donate at least one organ that's transplanted, not just donated, and this will be expressed not as a percentage of eligible deaths, but by what's thought to be a more broadened definition and objective measure of a potential donor, that is, someone under or at the age of 75 who died with a diagnosis consistent with organ donation as defined by ICD-9 codes through electronic medical records. It's hoped that this change alone could increase organ donation by as much as 5,000 per year. The next specific metric that will change from transplant rate, which is the number of organs transplanted per donor expressed as a fraction of eligible donors, will simply change the organs transplanted per donor expressed by the more hopefully accurate representation of a potential donor, that is, someone who's 75 or less who died with a diagnosis consistent with organ donation, and it's estimated that this change alone may increase the number of transplants by 8,000 per year. More interestingly, the OPO recertification changes are upcoming where the OPO recertification will be placed at risk, and OPOs will be adjudicated based on the performance tiers, based on the metrics that I just provided. OPOs in Tier 1, which will be the top quartile, will be automatically recertified. Those in Tier 2, which is defined as those that exceed medium performance but not in Tier 1, will not be automatically recertified, but will go through a more complicated process, but those in Tier 3, which are below the medium performance, will not be decertified. Effectively, OPO recertification will be placed at risk based on their performance under these new metrics, and centers that are underperforming are at risk for losing their donor service areas. The donor service areas covered by OPOs in Tiers 2 and 3 will be open for competition, and only Tier 1 or 2 OPOs can compete for these DSAs, and DSAs for Tier 3, that is, the underperforming OPOs, could be replaced. Now, there's potential problems with these OPO metrics. In talking to members of the OPO community, again, I pointed out that the definition of a potential donor will be broadened and more objective, but I think there's concerns that the accuracy of these definitions based on ICD-9 codes from EMRs may be in question. I think those of us who work within electronic medical records recognize the peril of this, and then the death data related to these designations is not available immediately and takes several years to be created. The other query or question is in the area of placing the OPO recertification at risk. In envisioning how this might happen, it's hard for me to envision how will this actually occur. If an OPO in San Antonio is underperforming and the center OPO in Dallas is overperforming, will that center essentially take that over? Will it liquidate the employees? Will it have the relationships within these new geographic areas to actually improve donation, or would this benefit the system, or would this create so much upending that it will create chaos and reduce donation? Members of the OPO community, I think, have concerns related to that. So, again, in summary, I provided you an overview of transplant metrics. These are measures and definitions of safe and effective care to hopefully improve and promote safe and effective care. They measure different phases of transplant, and they're an OPT and obligation under their charge from HHS. They're proposed changes for center metrics that are likely to pass and impact your transplant center adjudication performance, and these include four phases of care. Again, these may be implemented shortly, and these include a combined metric of organ acceptance, waiting list survival, 90- and 365-day graft survival, and finally, OPO performance metrics, which will go into effect in the next calendar year, will broaden and more objectively measure potential donors. It will measure organs transplanted, not just donated, and it places the recertification OPOs at risk based on their performance of those metrics. Thank you very much. Good morning. I'd like to thank you all for joining me today virtually. I wish that we could all be together in person, and I'd like to thank the organizers and Dr. Selsner and Dr. Izzi for inviting me to present on this important topic, discussing strategies to ensure inclusion and equity in liver transplant access. I have no relevant disclosures. So in talking about this important topic and strategies to ensure equity and inclusion in liver transplantation, I'd like to first discuss with you and review the social determinants of health and how they might affect access to liver transplantation, then discuss groups especially vulnerable to healthcare inequities in liver transplant, and ascertain points along the transplant journey where disparities may occur, and then identify potential strategies which may mitigate these inequities. So in evaluating mortality from end-stage liver disease, we all know that this has been increasing significantly over the course of the past few decades. However, what's really notable is that in this heat map of the United States, we can see that there are certain areas where it appears that mortality is becoming increasingly more prevalent, especially those areas of Appalachia, where there's known decreases in the access to healthcare. And this raises the question of how social determinants of health may affect liver transplant access. So what are social determinants of health? Well, in an ideal world, all patients would receive equitable access to medical care, including liver transplantation, based on their individual need. Unfortunately, however, we don't live in a perfect world, and non-medical factors influence healthcare outcomes, especially those that are related to what we call the social determinants of health. These include economic stability, neighborhood and physical environment, education, food quality and stability, community and social contact, and access to quality healthcare. And I want to break these down in particular as they relate to liver transplant. So in terms of access and quality of healthcare, or access to quality healthcare, referral to practitioners familiar with treatment of liver disease is important. And if patients are in an area where patients are unfamiliar with the care of end-stage liver disease, they may not get referred appropriately. In addition, those patients who live long distances from liver transplant centers may not be able to make appointments or be able to be transferred. And then these patients may also lack reliable transportation. There's also the issue of economic stability, which covers both the insurance coverage, as well as ability to afford out-of-pocket transplant expenses and the ability to afford stable housing and transportation. The neighborhood and physical environment affects the patient's ability to have safe and affordable housing, their community and social support, which is a necessity in terms of patients being evaluated for transplant and undergoing transplant, as well as public health resources, such as access to alcohol rehabilitation and drug rehabilitation programs. Education affects the ability to understand and follow instructions following liver transplant and the instructions in post-transplant medications. And it also affects the patient's ability to advocate for themselves and to seek out treatments for their own medical conditions. We all know that food quality and stability is important in maintaining our patient's health and access to special dietary requirements may be lacking in some areas, as well as resulting in overall poor nutrition and wellness. And this overall nutrition or malnutrition in these cases can affect the patient's immune health and their susceptibility to infections. Community and social contact is important as the patients who are undergoing transplant evaluation who are undergoing transplant must have a very good strong social support network in place. However, some patients may have multiple caregiver responsibilities, such as care for children or care for adult parents or other spouses. There also may be cultural, ethnic, and religious beliefs and attitudes, which may alter their consideration for transplant on the part of the patient and their willingness to accept transplant. So when we look at the schemata for the progression of a patient with liver disease from the time that they are diagnosed with decompensated cirrhosis or liver cancer to the time that they receive transplant and undergo post-transplant care, you can see here that there's multiple periods in which the social determinants of health may adversely affect their outcomes and their ability to proceed to the next step. In terms of the referral patterns for transplant, we've discussed access as well as referral. If a patient is never referred for liver transplant, they can't receive a liver transplant. The education of the patients, as well as a mistrust of providers in general among certain underserved populations and populations which have been especially vulnerable to mistreatment by physicians historically. After liver transplant evaluation and during the evaluation process, it is imperative that the patients are able to sort of qualify on a psychosocial standpoint in order to be good candidates for transplant. And this is where many of these social determinants of health may prove barriers to a patient being able to receive a liver transplant, including inadequate social support, lack of insurance, lack of financial security, the absence of an automobile in order to make it to appointments. And language barrier problems can also pose a threat to a patient being able to receive equal access just because of difficulties with communication with the patients. Once a patient is wait-listed for liver transplant and when they're undergoing liver transplant post-transplant care, issues such as food security, access to specialist, travel distance, communications, public health resources and education become more important. And we know that socioeconomic status and payer status are highly important in patient outcomes. And this has been shown not only in liver transplantation, but also in other surgical and medical specialties. Looking at a breakdown of the transplant patients in particular, we see that there is definitely ethnic disparity or racial disparity in terms of the percentage of patients that are being transplanted in their payer status. So the majority of white patients are insured under private insurance, whereas the majority of black and Hispanic patients have either Medicare or Medicaid with an increasing percentage having Medicaid. The other thing that becomes a question and becomes a problematic is the question of patients who don't have insurance or who have to receive their insurance through charity care or free care. There are very few transplant centers in the country. I know of one, which is my own center that will accept charity care as a payer for liver transplantation. There's been many, many articles which have evaluated this. I've outlined a few here, one being by Bryce in 2009, which demonstrated that patients with Medicaid only are less likely to refer to liver transplant than with other insurance. And then looking at the VA system, Canowal recently demonstrated that patients with low income or VA only insurance are less likely to receive transplant referral. And the most common barriers for referral are mental health and social barriers. Also looking at the VA system, Dr. Goldberg demonstrated the distance from the transplant center impacts the likelihood of referral in VA patients and the patients with a greater distance from transplant center also have a higher wait list mortality. So I wanna break down as well, some of the particularly vulnerable populations, those being women, children, and minorities. And I'm only gonna touch briefly on these because of the limited time that I have. In terms of women who are diagnosed with liver disease, looking at the annual increase, the women diagnosed with liver disease are actually disproportionately dying from liver disease compared to men, especially in the age groups of 25 to 64. Interestingly enough, only 38% of those patients who are currently listed for liver transplant in the U.S. are females. But when you look at the trajectory of patients being transplanted for liver within the United States over time, we see that men have a much steeper trajectory of transplant than women. And that this gap between men and women in the percentages of patients being transplanted is significantly increasing. So why is there this disparity? And I'm gonna touch on two of the most important reasons. First, I wanna visit the question of the MELD score and kidney function in women. So women have a higher incidence of death on the wait list, controlling for age, ethnicity, etiology of liver disease, region of transplant, blood type, diabetes, dialysis, and the MELD score. Part of this reason is a result of their kidney function and differences in their kidney function in comparison to men and other people who are listed. As we all know, creatinine concentration is affected by muscle mass. The muscle mass in women in general is much lower than it is for men. And overall in serotics, creatinine is not really a great mechanism by which to calculate their actual GFR. So in comparison to men at listing, women are known to have a significantly lower serum creatinine, which translates into a lower MELD score, but they also actually have a lower GFR at any given serum creatinine compared to men, which means that their risk for mortality is higher at any given MELD score. And how do we account for this? That's a very problematic issue. The other issue that we run into is the question of the impact of body surface area on sexual disparities. So the average height for men in the United States is five foot nine inches compared to five foot four inches for women. So as a result, size mismatch is much more common as a reason for organ decline in women than it is in men, with 16.8% of organ declines for women being due to size and only 5.3 being for size for men. And the reason for this is that size is very important from a technical aspect when doing the liver transplant. It's usually okay for us to put a smaller liver into a larger person. However, it's very difficult to put a larger liver into a smaller person because you run into significant issues with graft function following the transplant, as well as technical issues during the transplant itself. So as a result, primary offers for women of smaller stature are significantly more likely to decline than for men of small stature, just because the women just generally don't have as much space available. But interestingly as well, patients who are less than five foot five inches have been shown to be significantly more likely to die on the wait list. And 72% of women fall into that category. Another vulnerable population is the pediatric population. Reasons for disparities in pediatric liver transplantation also include size. Size mismatch accounts for 30% of declines of primary liver offers. In addition, there are a limited number of liver transplant centers available for pediatric transplants, which affects both the geographic availability, the distance of travel, as well as the experience of the centers that are performing the transplants. And interestingly enough, 40% of the pediatric transplants were performed at centers that do less than five transplants per year. And this can affect the aggressiveness of the center and their willingness to think outside the box in getting these patients things like split liver grafts. There's a greater geographic distance of travel for family and a greater financial burden on the families. There have been some recent changes in the allocation system to help direct pediatric donors to pediatric recipients. However, from 2007 to 2014, 5.6% of adult patients who were transplanted received livers from pediatric donors. There's also significant racial disparities and socioeconomic divide, which affect the outcomes in liver transplant. In terms of racial disparities, there's much research that's gone in to different racial disparities in transplant as well as an access to care. But interestingly enough, if you look at the cause of mortality by race, the liver disease is considered to be among men, the 10th leading cause of chronic liver disease. However, within the Hispanic population is actually the sixth leading cause of liver disease. So one might expect that there would be a significant increase in the Hispanic patients that were getting transplanted. However, when we look at racial disparities in terms of access, we see that both African-Americans and Hispanics have a significantly lower transplant rate compared with white patients. So social determinants of health often increasingly affect minority populations in terms of liver transplant access due to cultural bias, mistrust of medical establishment due to historic mistreatment, language barriers, and socioeconomic divides. Provider bias and referral of patients to transplants may also play a role and should be addressed. And increasing waitlist mortality is associated with decreased access to specialized care and food and those types of things. There's also some differences in terms of post-transplant outcomes that need to be addressed and people need to be aware of, including susceptibility to rejection, autoimmune disease prevalence, as well as metabolics of medications. So how do we fix these problems? Well, I'll be honest with you, I don't think that we can fix all of these problems because I think some things are just so ingrained within the transplant system that it's going to be impossible for us to address, especially when we have limited livers available for transplant. However, when we look at our progression of patients from the time of diagnosis of liver disease to the time that they receive their transplant, there are certain areas where we can focus our efforts. In the referral process, I think provider education and education to the community physicians regarding liver disease and the indications for transplant is extremely important. There's also important for us to establish outreach clinics in order to reach some of those populations that do not have readily accessible access to liver care centers. Community health fairs and our presence there can be very important, as well as instituting measures of telehealth. And during the global pandemic, one of the good things that's come out of this is increased access to healthcare through the use of telehealth and hopefully through advocacy of the AASLD as well as other societies, we'll be able to convince Congress to maintain some of these things following the completion or the end of the global health crisis. Following transplant evaluation while the patients, and prior to wait listing, it's important the center has cultural awareness. This can include hiring a multilingual staff, providing education materials in different languages, and also increasing the diversity of the providers that are present, including hiring of women and hiring of minorities. We can also institute things like outreach coordinators, which have been very effective in disease processes such as COPD, congestive heart failure and diabetes. Congestive heart failure and diabetes. And again, institution of broader telehealth practices as well as transparency among the EMR is important. And these factors also play a role in the patients who have been wait-listed for liver transplant and who are those who are undergoing post-transplant care. There's also been some targeted strategies that have been proposed to mitigate some of the disparities that we see within the listing practices. These two that have been recently proposed are the MELD-GRAIL system. GRAIL being GFR assessment in liver disease, which employs the EGFR using creatinine, BUN, age, race, gender, and albumin, and potentially is a better predictor of wait-list mortality in women, including subgroups of more critically ill women and older women. The MELD 3.0 adds gender and albumin to the MELD sodium and grants women an additional 1.3 points on their MELD score to make up for some of the sexual disparity. The MELD 3.0 in evaluation reclassified about 8.8% of decedents to a higher MELD tier. The AASLD has also been very active in advocating for mitigation of some of the inequities in liver transplant. The Public Policy Committee recently published a public policy piece to evaluate strategies for promoting equity in liver transplantation, including recognizing the stakeholders as well as potential action items, a lot of which I've already touched on here. But I wanna emphasize things like workforce training, education of the staff and implicit bias, diversification of the staff, hiring of people who look like some of the underserved populations, like some minorities as well as women, community-based outreach programs. These can alter the referral patterns and improve the access of patients from underserved areas to getting to the transplant center to be able to have their liver disease treated, preferably before they're super sick with a high MELD and needing to go to the ICU. Education, health fairs, early screening for liver disease, screening for hepatitis C, treatment early of hepatitis C so they don't develop cirrhosis in the first place, as well as we need to advocate for policy mandates such as telehealth, improved reimbursement structures for our physicians in order to improve their ability to take care of these patients in a directed and thorough manner. And we need to advocate for research to increase awareness of these potential inequities. So in summary, social determinants of health and inequities in vulnerable populations may impact access to liver transplant at all phases. Understanding of these inequities will allow us to develop strategies to minimize disparities and frameworks are necessary to minimize barriers and improve access. And I'd like to thank you, and I look forward to your questions at the panel discussion. Thank you for the opportunity of addressing the topic of transplant tourism in this course on contemporary considerations and controversies in the field of liver transplantation. In 2019, there were close to 150,000 solid organ transplants carried out in the world, which is indeed an impressive activity that however the WHO estimates that barely covers 10% of the global needs of patients. And the disparity between supply and demand of organs for transplantation has largely exacerbated in 2020 because of the COVID-19 pandemic with a substantial decline in the number of solid organs and liver transplant procedures carried out globally. We were particularly focused upon the issue of liver transplantation. In that same year, 2019, there were close to 36,000 liver transplants carried out in the world. But this activity was only performed by 70 countries throughout the globe. Only 70 countries provided liver transplantation services. And the activity ranged between less than one and more than 30 liver transplants per million population, which means that there is extreme disparities in the access of patients to liver transplantation activities throughout the world. This map shows the same information, the number of liver transplants per million inhabitants in 2019, where we already can see how there are two regions in the world where the highest activities, the highest number of liver transplant procedures are performed, which is basically North America, the United States in particular, and the European region. So how do these regions of the world deal with the liver transplant waiting list? If you're focusing in this table about the management of the waiting list for solid organs in the US and in Europe, and particularly on liver transplantation, you will see how in the US in one year, only 39% of patients who were wait-listed for a liver transplant received that liver transplant in that same year, and how 5% of wait-listed patients, more than 1,000 patients died while waiting for a liver transplant. And the figures are very similar in the European setting with around 1,000 patients, again, dying while waiting for a liver transplant. So if the two regions of the world with the higher rates of liver transplantation are not able to cover the transplantation needs of their own patients, we could easily conclude that there is no country that is self-sufficient in transplantation or in liver transplantation throughout the world. Now, this limited availability of liver transplantation and the disparities in the access of patients to liver transplantation or for solid organ across the world is the main reason why patients are compelled to travel to other countries to get a transplant. At the Global Observatory on Donation and Transplantation, every year, we inquire countries whether they are aware of patients who have traveled to other destinations to receive an organ. And you can see how there is a limited number of countries, 36 countries, that are able to provide this information. And of those, 31 countries reported that more than 700 patients traveled to other countries to get a solid organ transplant in just one year. So very few countries providing this information and just in one year, more than 700 patients were aware that more than 700 patients have traveled abroad to get a transplant. And you can see how the majority of these patients come from the Eastern Mediterranean region and particularly from countries in the Middle East. Now, of course, not all patients who travel for transplantation engaged in transplantarism. The Declaration of Istanbul defines that travel for transplantation becomes unethical and thus is transplantarism if the transplant procedure is performed in the context of organ trafficking or human trafficking for the purpose of organ removal and hence that transplant entails the exploitation of a vulnerable or when that transplantation undermines the ability of the country of destination to provide transplantation services to its own patients. We should remember that no country is self-sufficient in transplantation, which means that when non-residents access the waiting list in another country, they would be falling under the scope of what the Declaration of Istanbul defines as transplantarism. Now, for patients who travel for transplantation, how frequently they engage in transplantarism and in its different forms. Let me take you to this study that was performed in the Council of Europe by using RITA, which is called the Registry of International Travel for Transplantation. To build up this registry, the Council of Europe has asked member state to designate a national focal point in each ministry of health to deal with transplant-related crimes and to participate in this data collection, which is carried out annually. The national focal points in each member state of the Council of Europe every year gets into contact with the transplant centers to compile individual data from patients who have traveled to other destinations to receive a solid organ transplant. That information is collected by the national focal point and introduced in this international registry, which aims at defining or describing the dimension of this phenomenon and describing some qualitative aspects. Now, when every year we get this information from all countries around Europe, we classify patients into three different categories attending to a pre-specified algorithm. So patients may be classified as having properly traveled for transplantation, be suspected of having engaged in trafficking scenarios, or being accessing the waiting list in another country, and hence impairing self-sufficiency in transplantation. So during a four-year period, several European countries participating in this exercise have been able to identify more than 350 patients traveling to other destinations to receive a solid organ transplant. Fortunately, the majority — I'm sorry that this slide does not display properly — 60 percent of these patients have been properly traveling for transplantation. There are 22 percent of patients who have engaged into cases that could be consistent with organ trafficking, and there are about 18 percent of patients who have traveled to other destinations to access deceased donor organs. And this is the particular type of transplanterism in which I'm going to spend the next few minutes, basically the access of non-residents to deceased donor organs. The first thing that I would like to address from the perspective of countries of destination is with what frequency deceased donor organs are being allocated into non-residents. So first of all, let's go to the U.S. to a recent study that has been just published in Transplantation. The authors described the waiting list for liver transplantation and the actual recipients of liver transplants in this period of time and classified patients into three groups, citizens of the U.S., non-citizens, non-residents, and non-citizens who lived in the U.S. Particularly focusing on non-citizens, non-residents, we could see that they represented 1% of recipients of liver transplants during the study period, which seems a very small percentage. Importantly, in this study, the authors described that compared to the other two groups, non-citizens, non-residents were predominantly white males, highly educated, insured by foreign governments, privately insured or self-insured, and outstandingly, they were more likely to proceed to liver transplantation, and they were receiving the liver transplant in centers, which were well-known for having shorter waiting times. So it seems that non-citizens, non-residents in this study were a particularly privileged group, and please keep that into your mind for the further discussion that I will raise. Importantly, these authors put under question the reliability of this data collection. This is self-reported data as per an OPTM policy, but there is no cross-verification of this data, and there is no auditing of this data. So the authors understood the limitation of this classification and of this data collection. In Europe, for a given year, 2017, we also tried to estimate the number of recipients of deceased donor organs who were non-residents, and we reached a very similar result as the U.S., so 0.7 percent of recipients of deceased donor organs in Europe were non-residents. This percentage was a little bit higher in some countries like the Czech Republic, Austria, Italy, France, and the U.K., but was particularly high in Austria, where you can see how 6 percent of recipients of deceased donor organs were non-residents, and this is related to the fact that Austria has engaged in official cooperation agreements with neighbor countries, as we will see afterwards. But again, the authors of this study doubted of the reliability of this data collection. First, it was outstanding that several European countries were not able to provide this data, and second, because the quality of the data was put under question by some of the reporting countries. With some particular problems, for example, in my country, Spain, when patients have been living or individuals have been living in a country for a short period of time, they are administratively considered as residents, even if they have established their residency with the purpose of gaining access to the public healthcare system, and we will discuss this afterwards. So, based on what I said, even we're talking about 1 percent of non-residents in the U.S., 0.7 percent in Europe, we're likely just seeing the tip of the iceberg. We are likely addressing a more frequent phenomenon, but just don't have an accurate idea of what is the true dimension of it. Now, let's consider that these percentages were real, that we're just talking about 1 percent of recipients of our deceased donor organs being non-residents. Should we have a specific policy to address this? My answer would be yes, because of the many ethical challenges that this practice imposes from a number of perspectives. In the very first place, we know that this practice reduces the opportunity for residents gaining access to deceased donor organs, and residents are the ones that sustain the system. Remember that when we allocate an organ to a non-resident, there is another person on the waiting list who will not get that organ. And of course, this situation may undermine the trust of the resident population on the transplantation system. So this is an important reason why we should cope with this problem. Secondly, because the practice selects patients who travel, for those who are able to overcome the legal, administrative, and financial barriers to settling in another country to gain access to the waiting list. And the social injustice becomes even more evident when transplant is provided by the private sector just to those non-resident patients who have the financial means. The practice also deters countries of origin from making progress towards self-sufficiency in transplantation. In addition, when patients do not have access to long-term immune suppression and specialized follow-up care upon their return home, we are putting those patients and those organs under risk, and likely falling into what we could call a futile allocation of organs. And finally, when the transfer of care between centers and countries is not well-organized, we may be breaching transnational biovigilance, transnational traceability, which may entail a risk not only to individual health, but also to public health, particularly when there is a risk of transmission of infectious diseases. So for all these reasons, we should be developing a national policy. Now, this is not easy because in this policy, we should be addressing two things. On one hand, we need to address our primary duty, which is that of providing transplantation services to the resident population. But on the other hand, we should be also considering providing compassionate care for non-resident patients who do not have access or good access to transplantation in their countries of origin. I would like to give you a formula, but I don't have it. What I'm going to do in the next few minutes is to share with you the policies that have been put in place in different countries. In the very first place, and I have mentioned this before, in the U.S., this is the current policy in place, OPTM policy number 17 on international organ transplantation. I'm not going to read the details, but basically this policy is in place since 2012, and it replaces the previous 5% rule that triggered an audit when a center was providing disease-donor organs, where it was allocating the disease-donor organs to more than 5% of non-residents. At present, this order, this rule has been withdrawn, but right now the policy is that when a patient is waitlisted, it is mandatory to report the residency and citizenship status of that patient, and there will be a review of this data and a public report that will be performed on an annual basis. So the policy in the U.S. has been transparency, absolute transparency on residency and citizenship status. In Europe, we have tried to develop the study within the framework of the European Committee on Organ Transplantation, the CDPTO, which is managed by the Council of Europe, and we settled on a working group by which we performed a survey to collect information about these policies, and we had 28 European countries participating in this study. What did we learn from this study? Well, in these 28 countries, there were two countries who would never allow non-residents to access the waiting list. There were four countries that allowed non-residents to access the waiting list with no restrictions, so there were no restrictions at all, and there were 22 countries that would allow non-residents to access the waiting list, but under very specific conditions. I'm going to summarize these conditions and these policies across Europe in these 22 countries. In the very first place, we noticed that a majority of countries would allow non-residents to access the waiting list when they were already present in their jurisdiction if they were in a situation of special clinical or social vulnerability, just for humanitarian reasons. These were, in 16 countries, patients under urgent life-threatening conditions that could only be treated with transplantation. In five countries, minors would be immediately given access to transplantation if they were in need, and in eight countries, refugees and asylum seekers, which makes sense because these patients do not have any other alternative to gain access to transplantation. What were the policies outside of this situation of special clinical or social vulnerability? Well, in some countries, particularly in Belgium, Croatia, Italy, and France, patients from other countries are allowed to access the waiting list after approval by specific committees that attend to certain requirements or conditions. For example, that there is a formal referral by a national authority, that they have evidence that the transplant is not possible in the country of origin, for example, because of its complexity or because that transplant program is not available at the country of origin, evidence that the patient has not been wait-listed in another country, that there is financial coverage for the transplant procedure, and that the patient will have proper follow-up care when that patient returns to their home country. So this is a policy to accept patients from other destinations under the system of waiting list outside or besides the particular conditions or situations that we described in the previous slide. Now, the majority of countries in Europe, particularly 15, prefer to give access to non-residents to the waiting list when they are engaged in official cooperation agreements with other countries. This policy applies in 15 European countries, and these official cooperation agreements are based on the concept of reciprocity with shared benefits and shared responsibilities for the two countries involved. Reciprocity is understood as a broad concept. For example, in Austria or in Spain, these official cooperation agreements have been established with neighbor countries that contribute to the disease donor pool, for example, in lung transplantation. Patients are accepted in the waiting list for lung transplantation from other destinations, but these countries will be providing lungs to the teams in the country of destination. But for example, Croatia, on the basis of political and historical reason, has established cooperation agreements with neighbor countries by which patients are accepted on their local waiting list but with the commitment of the country of origin of developing a disease donor program under their tutorship in a specific period of time. And finally, there are several countries, seven countries, which allow non-residents to access transplantation after a minimum period of time living in the country, but because this is the minimum time by which they will be gaining access to public healthcare as a whole. This period of time, as I mentioned before, is as short as three months in Spain or six months, for example, in Belgium, Cyprus, or Slovenia, to give you some examples. There are no limits or quotas to transplant non-residents applied at present in any European countries. So I have provided you with an overview of these policies. What would be my concluding remarks? First, because no country is self-sufficient in transplantation, the access of non-residents to the waiting list is or should be a common concern for transplant authorities and for professionals across the globe. The dimension and the impact of this phenomenon cannot be accurately measured. So it is imperative that every government and every country makes efforts to collect precise information on the citizenship and residency status of patients when they are wait-listed for transplantation. Very importantly, each country should define transparent criteria for non-residents being entitled to access the waiting list. In my view, this decision should not be left to individual physicians or institutions, but be defined by national policies. Now, policies are very variable. There are discrepancies between countries in how to deal with this phenomenon, with this situation, but we have also seen common avenues that could serve as a reference and help us improve justice, equity, and transparency when confronting this phenomenon. I thank you very much for your attention. Thank you so much for inviting me to discuss about keys to maximizing wait-list survival. My name is Juan Pablo Ara, and I'm a transplant hepatologist and an assistant professor of medicine at the Pontificio Universitario Católico de Chile, the School of Medicine. I have nothing to disclose. The aims for this talk would be to discuss recipient optimization, especially frailty, sarcopenia, nutrition, and immunization, to discuss special groups such as ACLF patients and some disparities in prioritization, and to briefly discuss expanding the donor pool. So when I was preparing this talk, I posted on Twitter a question asking which are the keys to maximizing wait-list survival for patients with cirrhosis. Most people replied that improving sarcopenia and frailty, and second, that we need to increase the donor pool. I'm going to touch on these two topics. So the first topic is recipient optimization. One of the most important things that we have learned over the past years is about frailty and sarcopenia. So in addition to treat the underlying disease, aside the hepatic encephalopathy, et cetera, we can target sarcopenia. But how do we define sarcopenia? Sarcopenia consists in a loss of muscle mass, as well as muscle function and performance. Obviously, this concept is broader than cirrhosis alone, and much of the data is from non-cirrhotic patients. The research of sarcopenia and cirrhosis has been focused on muscle mass, mainly through cross-sectional imaging, with heterogeneity in the choice of measure and cutoff. So in regard to measures, various authors have used saw muscle thickness per spinal muscles and the total skeletal muscle index, L3. There are key several determinants for muscle mass and strength. A major one is sex. Men have more muscle than women. Ethnicity, African-Americans will have more muscle going down to Asians. And age, after the age of 50, our muscles will start losing mass at the rate of 1% per year. Muscle strength related to decrease in muscle quality due to fatty infiltration and conversion of muscle fiber from type two to type one. And how is that compared to muscle mass data in cirrhosis? This is a retrospective data, so limited in its interpretation. But looking at these, we can see that patient with cirrhosis lose muscle mass more quickly, even up to 6% per year in child C patients. How we do define frailty? And again, this is not exclusive for cirrhosis. For a global perspective, frailty is defined as a clinical state of decreased physiological reserve and increased vulnerability to health stressors. Looking at the graph, you can see how a robust cirrhotic patient can have added compensation, decreasing his functional capacity, but then bouncing back. If the patient is frail, will not have the capacity of bouncing back after the compensation and will go to a state of disability. In cirrhosis, it has been more studied the physical component, more the multi-component model. The pathophysiology is multifactorial and still more research is needed in this, but sarcopenia is the result of auto-obtaining balance between protein synthesis and degradation. And this is affected by inflammation, bacterial translocation, reduced dietary intake, significant reduction in physical activity, reduction on glycogen storage. So they mobilize muscle to produce energy and of course, ammonia and testosterone. How do we measure these concepts? Probably the most commonly evaluated is the liver frailty index, but also six minute walk and the gait speed. And to assess sarcopenia, as I told you, CT for cross-sectional images of muscle mass, which it has some limitation. So their options are being developed such as the thigh ultrasound, bio-impedance geometry or face angle. So basically the tool you pick will depend on your purpose, setting, expertise and access. This is a study from more than 35,000 showed that how muscle function correlate with survival. Here, gait speed was used to predict life expectancy. So all these predictors can be used in cirrhosis. Here, you can see how sarcopenia predicts survival in cirrhosis, independent of MELD scores. Similarly to this study by Dr. Jennifer Lai, showed that compared with MELD sodium alone, MELD sodium friability index, including hand grip strength, balance testing, and chair stand will which take like less than five minutes to do, better predict survival, adding up to nine points to the MELD score. In this study from my university, friability was independently associated with decreased survival in the long-term follow-up. Reduced gait speed was strongly associated with mortality and could be a surrogate marker of friability in clinical practice. So we can aim to improve sarcopenia by nutrition and exercise. First with nutrition, this paper from Dr. Tandon from Canada gave us the prescription. The first choice will be to use indirect calorimetry. However, we can use predictive equations for non-obese patient will be at least 35 kilocalories per kilogram per day. Protein for 1.2 to 1.5 grams per kilogram per day, and using late night snack, and also use brain-chained amino acids, especially in those who are protein intolerant, or unable to meet protein targets. This randomized control trial from India showed that nutritional intervention improved minimal hepatic encephalopathy at six months, 71 versus 23% compared to control, and also significant improvement in quality of life, muscle mass, strength, and reduced hospitalizations. The next step in management is exercise. Exercise increase physical performance, quality of life, muscle strength, muscle size, and also reduce portal pressure in patients with cirrhosis. Some liver transplant centers have implemented formal prehabilitation programs. So the recommendation in resistant training is at least two days per week, anaerobic activity three to five days per week, aiming to target at least 150 minutes of moderate activity per week. Obviously, in those patients that are very deconditioned, working with a physical therapist is best, starting for a slow and increasing the intensity. This point is very important. In this study from the New England Journal of Medicine, you need to acknowledge that when calories are restricted, 75% of weight loss is fat and 25% will be muscle. So always prescribe exercise if you are prescribing weight loss. Combination aerobic and resistant exercise with diet seem to be the most effective in improving physical performance. And what about pharmacotherapy? Nothing really ready for the prime time, but testosterone has a randomized controlled trial that demonstrated benefit in increasing lean mass, bone mass, and reducing fat mass. However, no impact on muscle function or quality of life in this study. The big question is whether prehabilitation or pharmacotherapy aiming sarcopenia improve outcomes for liver transplant. There are a few ongoing trials on this, and we should be able to have more information in the near future. Another important topic is vaccines, especially for serotics. There are immunizations recommended for patients with chronic liver disease. This is by the CDC. There is still research to be done regarding the efficacy and best timing for vaccines in the liver transplant study. And this is very topical during this pandemic. And this is a study from Germany that analyzed the response to COVID vaccine amongst patients with cirrhosis and liver transplant recipients. They found that after the second dose of vaccine, seroconversion was achieving 63% of liver transplant recipients compared to 100% of serotics and controls. Furthermore, a spike specific T cell response rate were 37% for liver transplant patients, 65% in serotics, and 100% in controls. Altogether, 28% of liver transplant recipients did neither develop a humoral nor a T cell response after second dose of vaccination. So this data support the third dose in this patient. The other big topic is how to address disparities or consider specialist groups in organ allocation and prioritization. The first group is patient with ACLF. Although this is a matter of debate, patients with ACLF have increased mortality, so we need to somehow acknowledge it. In this study from 2019, using data from the UNOS registry, they compare liver whiteness mortality or removal according to a MELD score and ACLF category. They found that patients with ACLF-3 were more likely to die or be removed from the whiteness, regardless of MELD sodium score compared to the other ACLF groups. The proportion was greatest for patients with ACLF-3 scores and MELD sodium score below 25. So certain patients with ACLF-3 have poor outcomes regardless of MELD sodium score. So liver transplantation increases the odds of survival in this patient, particularly if performed within 30 days of placement on the waitlist. Mechanical ventilation and liver transplantation and use of marginal organs were associated with increased risk of death. More recently, this study showed that among candidates listed for transplantation with ACLF listing, MELD score and ACLF interact and predict cumulative risk 90-day waitlist mortality. The impact of ACLF grade on 90- day waitlist mortality is much higher at lower MELD score, especially below 25. The authors proposed a novel scoring using MELD score and ACLF grade uplisting as most accurate 90- day waitlist mortality. So in summary, the data showed that patients with relative low MELD score, meaning below 25, had high mortality rates ranging between 30 to 40% if they had ACLF grade 2 or 3. It will need to be discussed whether this patient should get some prior prioritization with certain criteria. Just a few words regarding special groups. Recently, it was published that MELD 3.0 score, which was updated with contemporary data. Number two, creatinine maxing out three milligrams per deciliter. And number three, female sex and low albumin adding to the score. The later only if low creatinine. This score was intended to reduce disparities in prioritization in certain groups and we will need to see how this score is able to change disparities. And finally expanding the donor pool. Obviously, we will need to increase the number of donors if we are increasing the number of recipients to reduce the waitlist mortality. I want to spend my time on this because in session number three, Dr. Amelia Hitzheimer is going to talk about measures to maximizing graft potential. But one option is maximizing disease through deceased donor after cardiac death, split liver, marginal livers, or machine perfusion systems. Another option is increasing donor pool through living donor liver donation. For example, in Chile, we were able to reduce almost by half waitlist mortality after the introduction of a living donor liver transplant program. I thank Dr. Martin Deep for sharing this data. This can be very good alternative countries with low donation rates. During the next session, Dr. Ji from Korea is going to talk about how to safely maximize living donor liver transplant. And maybe in the future, we are going to be able to have artificial liver to increase the donor pool. So in summary, frailty and sarcopenia are common in patients with cirrhosis and impact the waitlist mortality. Nutrition and exercise, immunization and identification of high risk mortality groups are likely to improve waitlist mortality and strategies to increase donor pool are key. The key question that remains to be addressed in the future are to assess whether sarcopenia management, especially rehabilitation or pharmacotherapy improves post liver transplant outcomes. Also to define and assess the performance of a scoring selected groups and to tailor strategies to local donation rates on culture. With this, I would like to thank again for the invitation, I will be happy to take questions. Good afternoon, everybody. First of all, I would like to thank the ILTS and ASLD for the kind invitation. And I have no disclosure. For 40 years, we can observe demographical changes worldwide. Indeed, people are living longer. As in, as for instance, in the 80s, 55% of the population was over 65 years. And now it's 10%. The weight is also increasing. In the 80s, 30% of the global population was overweight with a BMI over 25. And now it is 40%. In the next decade, age and weight will still increase. And it is likely that at least 20% of people worldwide will be over 65 years in 2050. And that at the same time, overweight and obese will represent more than 50 to 60% of the global population. People are living longer. And we know that in parallel with aging, there is an increase of specific diseases. You can see here in this US study that from 65 years, there is a dramatic increase in heart disease, diabetes, and cancer. As aging, overweight and obesity are associated with specific diseases. And you can see here in a very large population of 3.6 millions of people, that from a BMI of 25, there is an increased risk of coronary artery disease, but also stroke and cancer. In parallel with demographical changes in global population, there are also changes in the epidemiology of chronic liver disease. For instance, in this US cohort, you can see that since the 90s, alcoholic and chronic hepatitis B seem to remain quite stable, while the prevalence of chronic hepatitis C dramatically decreases, and contrast NASH dramatically increases. It's important to note that in the next future, as you can see here, decompensated cirrhosis and liver related death associated with NASH will continue to dramatically increase all over the world. Thus, logically, indications for liver transplantation change over time. You can see on your left that in the US, indication for NASH increases and indication for HCV decreases. This is exactly the same trend in Europe, as you can see on your right. Please note that NASH represents quite 40% of indication for liver transplantation in the US, while it's less than 10% in Europe. Profiles of candidates for liver transplantation are also changing. When you look on this graph, you can see that recipients are older. On your left, in the US, the proportion of recipients over 65 was 9% in 2000, and is now 20%. Similarly, in Europe, on your right, there is a 16% increase in recipients over 65 between 2012 and 2016. Recipients become also fatter. And you can see here that in the US, there is a progressive increase in BMI. And it should be stressed that 35% have a BMI over 30, and 70% over 25. So here is the typical candidate for liver transplantation in 2021 in Western countries. Age over 60, obese, with decompensated NASH, diabetes, hypertension, at risk for coronary artery disease, chronic kidney disease, and non-liver cancer. Thus, the question is, is it acceptable to transplant this patient? And how far to push the limits? Liver transplantation can be seen as a patch on a tire. It does not solve everything. Indeed, liver transplantation fully reverses liver disease and its complication, but it does not rejuvenate and it does not reverse comorbidities. And even though it worsens all comorbidities due to the side effects of immunosuppressive drugs. Regarding age of recipients, several studies have reported the results of liver transplantation in oldest patients. And you can see here the largest series from both US and Europe, showing that five-year survival of recipients over 70 years is significantly lower than survival of those below 70 years. Interestingly, there are differences in terms of post-transplant outcome according to the severity of the liver disease. Here, patients with MEL score below 20, survival is similar whatever the age of the recipient. Here, patients with intermediate MEL score between 20 and 27, there is a trend for poor survival in recipients over 70. And here, MEL over 28, and clearly survival is worse in the oldest. By contrast, the presence of hepatocellular carcinoma does not seem to influence the survival in the oldest patients. You can see on the studies as patients over 70 have the same survival with or without HCC. And please note that in this series, five-year survival of patients over 70 is poor, below 60%. Older patients are at risk for cancer. And you can see here the risk for alcoholic associated cancer on your left, and for obesity associated on your right, according to age in a very large US population. The risk clearly increases after 65 years. The percentage increase for non-liver cancer after liver transplantation in oldest recipients is not exactly known, but it is probably very high. And to summarize, patients over 70 years have poorer post-transplant survival, especially when they have been transplanted for decompensated cirrhosis, and they are at high risk for non-liver cancer. Now, what about obesity? We know that obesity impacts pre, peri, and post-liver transplantation period. Before liver transplantation, obesity increases the risk of metabolic and cardiovascular comorbidities, as well as cancer, and these risks are still present after transplantation. Obesity is also associated with increased risk during surgery, with both surgical and anesthesiological difficulties, as well as risk of infection. Results of liver transplantation according to pre-transplant BMI are discordant in the literature. For instance, on your left, you can see that five-year survival is similar in different classes of obesity. In contrast, series on your right reports poorer results in patients severely or morbidly obese. And not surprisingly, the cause of death in this series was cardiovascular events in more than 20% of patients. Other conflicting results have been published in this field, and neither EASLD nor EASLD make any strict recommendation regarding the maximum acceptable BMI for liver transplantation. I would like to stress to the fact that the assessment of overweight and obesity is difficult in this population. BMI is usually considered as the reference. However, in decompensated cirrhosis, there is frequently fluid overload. And interestingly, in one study, correcting BMI for ascites resulted in moving 11% to 20% of patients into lower BMI classes. And most interestingly, the type of fat distribution has not the same impact on post-transplant results. Indeed, it has been shown that visceral adiposity, but not peripheral adiposity, was associated with increased mortality after liver transplantation. Thus, other tools than BMI should be used, and sarcopenic obesity and its impact on post-transplant outcome is one of the most promising and should be evaluated. Diabetes in candidates for liver transplantation is highly prevalent, between 30 to 70%, according to the series, and is associated with post-transplant complication. Its prognostic impact is directly related to its complication, especially cardiovascular and renal disease. Cardiovascular diseases are also frequent in this population from 10 to 50%, according to the series. Risk factors are well known and include metabolic syndrome, but also NASH and HCV infection. You can see on this figure that coronary artery disease is more frequent in NASH, and that the disease is more severe with a higher proportion of three injured vessels. Cardiovascular diseases are associated with periphery and post-transplant morbidity and mortality, and thus extensive workup is needed. In this large series, coronary artery diseases has only a mild impact on post-transplant outcome, whatever the severity of coronary artery disease, and even in patients who had revascularization before transplantation. Thus, coronary artery disease is not a contraindication for liver transplantation, maybe unless in patients in whom percutaneous revascularization is not possible. Now, just a few words concerning chronic kidney disease. Its prevalence is unknown in candidates for liver transplantation. It's probably high and more frequent in those with NASH because of risk factors common to both, namely diabetes, obesity, and hypertension. We know for a long time that pre-transplant, the chronic kidney disease before liver transplantation has a negative impact on post-transplant outcome in terms of both morbidity and mortality. When you look at the figure, you can see that patients with chronic kidney disease have poorer survival than those without, unless combined liver and kidney transplantation is performed. I would add that chronic kidney disease is difficult to diagnose, especially in patients with decompensated cirrhosis and large ascites, and that end-stage kidney disease justifies combined liver and kidney transplantation. Finally, we probably should pay greater attention to the dish than the ingredients. I mean, we should evaluate a global risk score rather than each comorbidities, which are all closely linked. The modified Charlson Comorbidities Index has been proposed more than 10 years ago, and as you can see on the table, the pre-transplant comorbidities associated with post-transplant mortality, and on your right, mortality according to known one or two or more comorbidities. Unfortunately, this score has not been extensively validated and is not used. So, here are my take-home messages. Changes in profile of liver transplant recipients due to both demographical changes in general population and epidemiological changes in liver disease, especially an increase of prevalence of NASH. Liver transplant recipients are getting older, increasingly obese and diabetic, at risk of cardiovascular diseases and or cancers, and all these comorbidities usually worsen after liver transplantation. Recent progress in the field of liver transplantation offers the possibility to push the limits regarding selection of candidates with comorbidities. Liver transplantation in patients over 70 years is questionable. BMI as a marker for obesity is not accurate, and clearly studies should evaluate sarcopenic obesity as well as its impact on post-liver transplant outcome. A global score of comorbidities is lacking, and liberalizing candidate selection would not be an issue in the absence of organ shortage. Thank you for your attention. Under well-established selection criteria, the outcomes of living donor liver transplantations are excellent as level one evidence. You may want to safely extend the indications of live donors. and paired recipients by experience center's experience. They say that the outcomes of living donor liver transplantation is overrated because the indications of living donor liver transplantations were very limited in both donors and recipients. Please allow me to introduce myself and today's subject. I'm Yi from Seoul National University Hospital. We have more than 2,000 cases experience of living donor liver transplantation over 20 years, and SNUH is one of the most innovative centers in the world. Today, I want to share my experience regarding how to safely maximize living donor liver transplantations. I have nothing to declare. In my center, the first half 10-year changes were as followings. Proportion of pediatric cases were decreased, and adult cases were increased more than 95%. Accordingly, live liver transplantation was main procedure, and donors were mostly offspring of recipients. In the strict criteria of fatty liver, fatty liver control program was applied most cases of moderate degree of fatty liver disease. We accepted more aged donors more than 50 years old, but donor age became younger because they are most of offspring. In terms of operation, we applied more left donor epitectomy, more than one-third, operation time, or stress state, and complication rates were significantly decreased. The second 10 years were a very exciting period to extend our open-donor hepatectomy experiences to live surgery. Two donor surgeons of my center are seniors, but they love to do something new. Since 2015, we have exclusively performed pure left donor hepatectomy. Until this year, 400 cases of left donor surgeries were accumulated. Throughout this period, donor characteristics have not much changed, but donor age was more than 33 years, even though majority of donors were offspring, which means the age of recipients are getting older. The mean operation times of period 1 to 3 were decreased from 5 hours to 3 hours. The time of extraction of liver graft was also decreased from 3 hours to 2 hours, the stress state from 8 days to 7 days. We do not reject donors with anatomical variations for left donor hepatectomy. Thus, these patients were referred from the whole nation. For this reason, anatomical variation rates were higher than expected. The number of multiple hyaluronic structures were well-matched between two time points, before and after operation. This means the multiple openings were not related to technical pitfalls of left surgery. With this background, the donor complication rates were around 6%, which were like 2012. In detail, however, the complication rates were decreased from 10 in the first 100 cases of period 1 to 3% in the last 100 cases of period 3, and major complication rates were around almost 0%. The recipient outcomes were also excellent, and the 30-day mortality was around 3%. Then, what was the long-term donor outcome? We reported Korean LDLT donor long-term outcome this year. More than 10,000 donors were analyzed and compared to control groups. This is age-sex-matched group, and this is healthy control group, which is similar to organ donors. For this healthy control group, people who have contraindication to be a live donor were excluded. The cumulative mortality rate of live donors for 10 years were 1.1%, and 1.5% in general population, and 0.3% in healthy control group. So, overall risk of death in live donors were significantly lower than general population, but higher than healthy control. Even more, the most common cause of death in healthy control group was suicide, and these red bars indicate suicide. This can be happened even 10 years after donation. The following were cancers and liver disease. When compared to health control group, donors have a higher risk of death except those aged 40s, a risk of death for those aged 50s, and a risk of death for those aged 60s. The risk of death from suicide and cancer were significantly higher in donors. Technically, we should well select those living donors, no coercion, legal age, APU compatible, born healthy, both mind and body. Ideal liver donors should have enough graft volume as well as remnant volume, but they should not have steatosis nor inflammation. But rare donors are rare. Best we push the boundaries of living liver donors a little bit, considering both donor and recipient safety. Age 65, moderate steatosis, grade 1 NASH, remnant 30%, GLWR 0.6%, anatomical variations, APU incompatible, ASA positive pair, CAR positive graft, and controlled medical and surgical histories. However, still we do not accept the followings, HLA one-way homozygote donor, metabolic liver disease, chronic hepatitis, HIV positive, and cancer history for pediatric liver transplant recipients. Let's start with the age of donors. Evidence showed protectomy outcome because of lower regeneration capacity and many co-medical issues, as you know very well. According to this report from Japan, show the six-month recipient survival rate according to the donor age. As you can see here, the recipient's outcome of donors in 20s was the best. But the recipient's outcome of donors in 60s was not that bad. This couple were in their 70s when they underwent donor hepatectomy and transplantation. They are now happy in their 80s. In Korean national data, donors more than 60 was only 5%. However, donor age more than 60 is not good enough for transplantation. In Korea, the age of donors in 60 as well as non-occupation and divorce status was the independent risk factor of donor death. The elderly living donors are healthier and younger with a short ischemic time compared to those in DDLT, but they can give only a half liver and keep only one-third of the liver. If you want to push the age-up limit in your LDLT program, you should be cautious in selection. Social support, bring them to more than 30 with minimal hepatic pain and without hepatic change. Recipients should have more GLWR, less sick conditions could guarantee the better outcome. Okay, in number two, steatosis. Steatosis is not a risk even although LDLT has younger donors and short ischemic time, but donor safety is an issue. To select proper donors, the evaluation protocol of my institution is complex. It starts with interview and followed by medical, ethical evaluations, as well as document processes. The medical details are included in this box, maybe similar in many LDLT centers. My center liver MR protocol is awesome. So, this will save liver biopsy and gland geography as an optional evaluation. Assessment of fatty liver was done through biopsy in the past. Recently, we can quantify the extent of fatty liver through MRS in my hospital with 95% sensitivity, as well as quantification. Fibrosis related to fatty liver can be assessed in MRL astrography with 85% sensitivity. Biopsy can give information of only one point of the liver, but MR, the whole liver. In addition to MR colon geography and 20 minute delayed gadoxinase image, intraoperative IV ICG injection gives a real-time accurate information of a uterine tree and cutting point. Okay, back to steatosis. We developed weight reduction program, actually, fat reduction, calorie reduction, low-carb diet, and vigorous exercise. After weight reduction, MRS was repeated to see whether fat fraction decreased below 8%. The success rate of this program was 40%. Patients more than 40 or with initially severe steatosis have high chance of failure in this program. The second, RISD self-succored a few of these patients with BMI more than 30 was not a risk factor for development of postoperative complication in elective surgery. High BMI donors are not so common in Asian countries, but recent data from Toronto and my institution showed well-selected high BMI donors, so-called healthy obese patients, without metabolic issues, nor fatty liver, and less than 60, can safely donate their light red liver. Left donor hepatectomy showed non-inferiority of the BMI donor. Left donor hepatectomy showed non-inferiority in surgical outcomes among these patients. The third topic is to use a small, full-size graft. Small, full-size graft is associated with inferior medium-term, but not long-term graft survival. Instance of small, full-size syndrome detected in recipients of small, full-size graft ranged from 0% to 11%. Poor outcome was related to high male sarcopenia of the recipients and aged fatty left liver donors. Smaller graft could be accepted for living donor liver transplant with appropriate flaw modulation, better outcome reconstruction, and surgical innovation like APORT, including resection in partial liver transplantation with delayed total hepatectomy. Okay, let's move with the number four, issue of HLA in living donor liver transplantation. Liver surgeons have less sensitivity to HLA in immunology like a liver. Thus, I will show it through a transcript. Even in living donor liver transplantation settings, we evaluate the HLA typing in DSA's frame. It's not for mismatching, but it's for exclusion of one-way matched homozygous living-related donors and to make a selective desensitization in highly sensitized patients. As you know, DSA-positive recipients have lower survival outcome than others. This photo shows positive C4D immunostaining of post-transplanting 10-day protocol biopsy without evidence of acute cellular rejection. Patients requiring DSA desensitization are high-male or small, full-size graft with a high DSA titer. Desensitization protocol was adopted from avian incompatible liver transplantation with a protocol composed of Ritux and plasmapheresis before transplantation in elective LDLTs. Other concern of HLA is post-transplant GFHD in liver transplantation recipients. This can be happened during massive destruction of the host-producing self-anogen to host APC plus large amount of donor lymphocytes plus poor recipient condition. This is rare complication but usually fatal, causing fever, cytopenia, diarrhea, skin rash, and super-super liver function test. One of the risk factors of GFHD is one-way matching homozygous donors in living-related liver transplantation. For this reason, we should check HLA typing for donor selection. In this family, father is a recipient and son is a donor. Son's HLA is one-way matching homozygote. Thus, the AC recipient does not well recognize the AA liver graft as a non-self, but the AA graft does recognize the AC recipient's organ as a non-self. For this reason, the AA liver attacks this AC recipient's marrow, uremicosa, and skin, which consists of natural barrier of human body. The most common cause of death in GFHD liver recipients is infection. The mortality rate is almost 100%. Okay, the number five issue is core positive donors. This is considered as marginal donor even in disease-donor liver transplantation. Because anti-HP core positivity means a sort of occult infection. However, happy DNA in these patients was not always detected in the liver tissue. On the other hand, the short-term outcome of these donors are not inferior to others in right liver endotectomy, but the lifelong outcome is not reported yet. Fortunately, the liver-related complications such as HCC, cirrhosis, and viral reoccupation differ significantly between these different groups. Most living donors with core positive serum was related to these green boxes. The number of happy infection rates were known as up to 25% in happy live patients. This can be reduced to less than 5% with prevention. Post-transplantation prevention composed of active vaccination with backup HVIC or lifelong HVIC injection or oral antiviral agent. De novo happy can be treated as chronic happy, and the treatment response rate is much better, around 60%. The before transplantation adaptive immune transfer via poster vaccination to live donor can reduce the de novo happy infection. And donor antibody titers more than 1,000 were related to lowering de novo infection. Finally, I'd like to recap today's my talk. We can push the boundaries of living liver donors a little bit, considering both donor and recipient safety. However, we cannot try these extended criteria at the same time. If you take one risk, you should keep others safe. According to center's experience in surgical and medical innovation, we can safely extend the LDLT criteria. This time, I focused on donor extended criteria. Technical things including remnant liver volume, around the 30% and anatomical variation of donor size can be dealt in surgeons' society. If your incompatibility in liver transplantation is still an unsolved issue, and another side of how to maximize the living donor liver transplantation would be recipient's extended indications require more time to explain like acute liver failure, advanced HCC, and technical tips to overcome difficult anatomical hurdles in APOLT as well as recession in partial liver transplantation with delayed total hepatectomy, Please pick me up again for the next issues. Thank you for your kind attention. Hello, my name is Sophocles Alexopoulos and I am Chief of the Division of Hepatobiliary Surgery and Liver Transplantation at Vanderbilt University Medical Center. Today, I will be speaking to you about the surgical treatment of children with biliary atresia with an emphasis on liver transplantation. I have no conflicts of interest to disclose. Between two to 15% of neonates will have jaundice at two weeks of age with the most common cause being physiologic jaundice of the newborn or breast milk jaundice. However, only a very small number, approximately one in 2,500, will have cholestatic jaundice with biliary atresia being the diagnosis in up to 40% of cases. This cholestatic jaundice can be accompanied by a colic stools and dark urine. The resultant overall incidence of biliary atresia in the United States is thus one in 12,000 live births, making it a rare and difficult to diagnose condition in the early newborn. Historically, total bilirubin has been utilized as an initial screening test to stratify jaundice in newborns. Unfortunately, total bilirubin levels fail to discriminate neonates with biliary atresia from those without, as demonstrated on the left. However, quantification of direct bilirubin is highly discriminant in identifying neonates with biliary atresia, even at two days of life. Biliary atresia is a progressive fibroinflammatory disease of the bile ducts that can affect both the extra and intrahepatic biliary tree. Characteristic histopathology of the liver at the time of attempted surgical correction typically demonstrates bile duct proliferation, as depicted by the black arrows and bile plugs as demonstrated by the yellow arrow in the center panel. Note that some degree of fibrosis is already present on trichrome staining. Despite surgical correction, many patients with biliary atresia will progress to classic biliary cirrhosis as demonstrated on the rightmost panel with bridging fibrosis and nodule formation. Although numerous systems exist for the classification of biliary atresia, I find this one utilized by the French National Biliary Atresia Observation Study Group to be particularly user-friendly. Four unique anatomic patterns are described, as well as a biliary atresia splenic malformation subgroup. Types three and four, which account for over 80% of all patients with biliary atresia, both have atresia of the extrahepatic biliary tree at the porta hepatis. Almost 10% of the cohort also has a splenic malformation syndrome. A suspected diagnosis of biliary atresia is typically confirmed by the absence of opacification and visualization of the intrahepatic biliary tree at the time of operative cholangiography. As demonstrated here, a liver biopsy is also obtained during the procedure for histology. When a diagnosis of biliary atresia is confirmed in an infant without evidence of decompensated cirrhosis, the standard of care treatment is to perform a hepatic portoenterostomy, also known as a CASI procedure. This entails complete excision of the extrahepatic bile duct and anastomosis of the limb of intestine to the hilar plate containing biliary ductules. Many groups have suggested that the success of this procedure is dependent on an early age at intervention, optimally within the first 30 days of life. Unfortunately, the fibroinflammatory process progresses in the majority of children, necessitating a subsequent liver transplant. As you can see, survival with native liver post-CASI is strongly correlated with both the type of biliary atresia and the presence of splenic malformation syndrome. Patients with the most common type of biliary atresia, complete extrahepatic atresia, the type IV atresia, as well as patients with splenic malformation syndrome have particularly poor long-term survival with native liver. Overall, more than 75% of patients with biliary atresia will either need a liver transplant or die at 30 years post-CASI. In this study, 5% of patients underwent primary liver transplantation without ever undergoing hepatic portoenterostomy. Additionally, 9.2% of patients died after portoenterostomy without ever receiving a liver transplant. The indications for liver transplantation in patients with biliary atresia post-hepatic portoenterostomy include manifestations of decompensated cirrhosis, such as ascites, portal hypertension, and hepatic pulmonary syndrome, as well as manifestations unique to the hepatic portoenterostomy, such as recurrent cholangitis, and to young children, such as growth failure. A total bilirubin level greater than two milligrams per deciliter at three months post-hepatic portoenterostomy is a strong predictor of the development of these complications, including ascites and growth failure, and the need for liver transplantation within a two-year period. In the United States, we currently prioritize patients with biliary atresia in need of a liver transplant based on either a MELD score for those 12 years or greater, or a PELD score for children less than 12. Although the MELD and PELD score have some commonalities, components unique to the PELD score include serum albumin and the presence of growth failure. Additionally, children less than one year of age receive points to compensate for the challenges in finding size-appropriate donors for these small recipients. Donor livers are then allocated to recipients based on descending order of PELD or MELD score in a system of consecutive acuity circles centered on the donor hospital and based on the distance between the donor hospital and transplant center, until the donor liver is either placed or discarded. With our current system of allocation, the incidence of death on the liver transplant waiting list for a patient with biliary atresia is very low, well below 5%. However, the current PELD allocation system is based on data from a 1995 to 2000 cohort of patients. Significant changes have occurred in the practice of pediatric liver transplantation since that time, and the PELD score may need to be adjusted or recalibrated to better reflect current practices. In this study, we assessed risk factors for mortality in the larger and more contemporary UNOS cohort of children awaiting liver transplantation for the treatment of biliary atresia. In addition to increasing serum bilirubin, we also identified the presence of portal vein thrombosis and ventilator dependence, both of which are not reflected in the PELD score as important independent risk factors for wait list mortality. Currently, biliary atresia is the most common indication for pediatric liver transplantation in the United States, representing nearly a third of all cases. While the large majority of these children undergo liver transplantation prior to five years of age, there is a small tail of patients that undergo liver transplantation even into adulthood. Multiple different types of liver allografts are used in pediatric liver transplantation to accommodate the wide range in the size of children. Deceased donor grafts include whole livers or size reduced livers, in which a portion has been removed to better fit into a recipient abdominal cavity. Additionally, the left lateral segment can be split off of a whole liver, either in a living or deceased donor to obtain a graft from an adult suitable for transplantation into an infant or a small child as depicted in the middle of the screen and to the right. Pros and cons exist for the use of each type of liver allograft. While there are fortunately a limited number of pediatric deceased donors, this means that small children can wind up waiting a long time for a whole liver allograft. This is why split and live donor liver transplantation were pioneered. However, there is an increased technical expertise required to split and transplant a left lateral segment graft. A large portion of allografts are grafted from a small donor to a large donor. This is why split and live donor liver transplantation is preferred over split and live donor liver transplantation. Additionally, there is a cut surface that can bleed or leak bile perioperatively. Not surprisingly, the choice of graft is strongly correlated with recipient size. In this study of the UNOS registry, the percentage of recipients receiving a whole liver was 15% and recipients greater than 14 kilos. Correspondingly, the number of partial liver allografts progressively decreased with increasing recipient size. Over the past two decades, there have been small changes in graft utilization with a slight decrease in the use of deceased donor whole and size reduced grafts and an uptick in the use of living donor and deceased donor split grafts. Currently, 50% of pediatric liver transplants for biliary atresia are performed with a whole allograft and 20% are performed with a live donor allograft. Interestingly, there is an interaction between recipient size and type of graft with respect to vascular complications. In this modern UNOS cohort of biliary atresia liver transplant recipients, we found that the use of a deceased donor whole liver allograft in a small, less than seven kilogram recipient was associated with an increased risk of vascular thrombosis compared to either deceased donor partial or a live donor allografts. Presumably, this had to do with the requirement that the whole donor liver also be very small to fit into a sub seven kilogram recipient and factors specific to the small donor's vasculature increasing the risk of vascular thrombosis. Interestingly, as the size of the recipients increased, the vascular thrombosis rates for whole liver has decreased substantially to below those of other graft types. Such incremental advancements in the management and surgical techniques have resulted in significant error-related improvements in liver transplantation for patients with biliary atresia. This split registry data demonstrated a 10% improvement in five-year survival for patients transplanted prior to 2002 versus those transplanted after 2002. This corresponds with a shift from cyclosporine-based immunosuppressive management to predominantly tacrolimus-based immunosuppressive management, as well as progressive decreases in the rates of hepatic artery and portal vein thrombosis and infectious complications and early rejection. Small but continued improvements in patient survival continue even in the current era, reflecting ongoing refinements in the management of pediatric biliary atresia liver transplant recipients. With excellent long-term survivals, exceeding 90% even at 10 years. An important component in the perioperative management of pediatric liver transplant recipients is the prevention of vascular thrombosis. This is particularly important in small recipients with microvascular anastomosis at substantially increased risk of thrombosis compared to adults. To mitigate this risk, the majority of pediatric liver transplant programs have anticoagulation protocols in place in which a heparin infusion is initiated intraoperatively. Many programs, including our own, also administer antiplatelet agents such as Dextran and aspirin within the first week. Recognition of the importance of perioperative nutritional optimization has also resulted in aggressive nutritional supplementation in pediatric liver transplant candidates. As demonstrated here, over 50% of young children awaiting pediatric liver transplantation are receiving supplemental parenteral or enteral tube nutritional support. One important question has been if and how hepatic portoenterostomy impacts the outcome of liver transplantation for biliary atresia. This large study out of Brazil identified an increased risk of both biliary complications and intestinal perforation in recipients with a prior hepatic portoenterostomy when compared to children with biliary atresia who underwent primary liver transplantation. Why would this be? This is a picture from a recent liver transplant we performed in a one-year-old with biliary atresia status post failed hepatic portoenterostomy. The reason I am showing this is to highlight the degree of inflammation and adhesions present from the prior intra-abdominal surgery. Removing this liver requires an extensive division of the scar tissue, as well as separating adherent intestines and colon from the native liver. Whenever such adhesions are divided, there is a risk of intestinal injury to the limb draining the bile, infection, and perforation. This increased risk of infectious complications is something that our group also identified when we analyzed the California State Database of patients with biliary atresia. In this study, we found that the number of patients treated surgically for biliary atresia compared to primary liver transplant recipients, patients who had either a biliary drainage procedure, presumably a hepatic portoenterostomy, or a liver transplant after a prior biliary drainage procedure, were at increased risk of sepsis, bacteremia, and cholangitis. Had a greater than 90% survival at 20 years. Additionally, their long-term survival was superior to that of patients who had undergone a biliary enteric drainage procedure or who had undergone a salvage liver transplant after biliary enteric drainage procedure. What about patients with biliary atresia, status post-hepatic portoenterostomy, who survived with their native liver into adulthood? We know that the majority of these patients will have cirrhosis in its sequelae, and many will require a salvage liver transplant. When compared to adolescents with biliary atresia, adults undergoing liver transplantation for biliary atresia have significantly inferior patient and graft survival. The explanation for the inferior outcomes in adults is multifactorial. Despite similar indications for liver transplantation, adults are listed at a higher MELD score compared to adolescents, which may represent a potential delay in listing. Additionally, because of differential access to and increased competition for deceased donor organs for recipients greater than 18 years of age, adults have to wait a longer time and achieve a higher MELD score at time of transplantation. Simply put, they have to be sicker. So, despite the low weightless mortality for patients with biliary atresia awaiting liver transplantation, is there a way for us to better characterize risk of mortality? This is important to the field of pediatric liver transplantation, in which many patients receive exceptions to the PELD-based allocation based on the belief that the PELD score inadequately reflects their risk of mortality. Our group has created an updated mortality prediction score using the PELD score. The PELD score is a new mortality prediction score using previously published variables identified from the UNOS registry of over 2,000 patients listed for liver transplantation for the treatment of biliary atresia since 2002. The BAM score has improved performance compared to the currently utilized PELD score. Our hope is to use the BAM score to better model mortality risk at 30, 60, and 90 days and decrease exception use for patients. So in summary, biliary atresia is the most common cause of neonatal cholestatic jaundice. Hepatic porto-neurostomy and liver transplantation are the only treatments resulting in long-term survival. Hepatic porto-neurostomy remains the initial treatment of choice in the majority of patients, but nearly 75% of patients with biliary atresia will require liver transplantation during their lifetime. Excellent long-term survival is achievable with liver transplantation during childhood. And advances in liver transplant prioritization and perioperative management, including surgical techniques, anticoagulation, nutrition, and immunosuppression have resulted in continued improvements in outcomes. Thank you very much for the opportunity to give this lecture. Thank you. Hi, my name is Scott Biggins, and I'm really excited to be here to speak to you about integrating serum sodium into the decision-making to take your patient to the OR when a liver graft comes available. Do wanna thank the course organizers for the invitation. I really do appreciate that. I have no disclosures. When considering hyponatremia and cirrhosis, it's important to assess whether or not that hyponatremia is either acute or chronic. Acute occurring within 48 hours and chronic beyond 48 hours. Next, assessing the patient's volume status is important. So is that hyponatremia related to hypervolemia, hypovolemia, or is the patient euvolemic? Most common circumstance in cirrhosis is chronic hypervolemic hyponatremia, and this presentation will address that predominantly. Hyponatremia is common in cirrhosis, particularly with ascites, and in this large European study was present in 22% of patients. Hyponatremia is part of the natural history of cirrhosis and portal hypertension, as you can see by this slide. As serum sodium retention occurs with portal hypertension progression, you can see there's often progressive reduction in GFR and refractory ascites, hepatorenal syndrome, and along that spectrum, a drop in the serum sodium. Shown here is the pathophysiology of cirrhosis and portal hypertension, and you can see with splanctic vasodilatation, arterial underfilling, activation of vasoconstrictor and antidiuretic factors, you can get dilutional hyponatremia. Serum sodium is a strong predictor of mortality in cirrhosis and is shown to be a strong predictor of weightless mortality as well. Shown here is the association between serum sodium and the risk of death, with a 13% increased risk of death per decrease in serum sodium. Based on this observation that serum sodium predicts death on the liver transplant weight list, serum sodium was incorporated into the MELD score and used for liver transplant allocation in the United States beginning in January 2016. There've been several changes over the last two decades in liver transplant graft allocation and distribution, and they are shown here. I'm just highlighting the MELD sodium implementation in January 11th, 2016, and then the consideration of a third iteration of the MELD score called MELD 3.0 that'll be out for public comment from UNOS in the next several months. MELD 3.0 will also include serum sodium, but it additionally will include sex and likely serum albumin. Shown here are the US allocation and distribution system that incorporates serum sodium into the MELD sodium score as well as the QED circles. When a liver graft comes available, it's first offered to those who are status one within 500 nautical miles of the donor, and then the liver graft is offered based on the MELD sodium score. You can see here the first tier for MELD sodium is 37 or higher, then progressing down to 33 or higher, 29 or higher, 15 or higher, and then out to national candidates and then back to those more locally with MELD sodium of under 15. So one question that's important to understand is what was the ramifications of this policy? The next several slides will address that. So implementation of MELD sodium reduced the wait list mortality and increased the rate of liver transplantation. The reduction in 90-day wait list mortality was 26% in the timeframe of this study. Shown here is a time series histogram of those patients going to liver transplant and their serum sodium at the time of transplant. You can see that the expansion of the green portion of the bars demonstrates the mild hyponatremia present in patients going to liver transplantation. The blue portion of the bars represents an increasing in the proportion of patients going to liver transplant with moderate or severe hyponatremia, so under 126. Importantly, the patients who are going to the operating room with higher MELD scores are having lower serum sodium. So this is a particularly relevant discussion to have about what to do with your patient who has low serum sodium, who's being offered a liver transplant graft because that's happening more often nowadays and I would expect that to continue into the future. So what happened after implementation of MELD sodium with regards to outcomes of liver transplant? There was no change in patient survival or graft survival as shown by this plot that includes both patients that had MELD exceptions when those were transplanted under their lab MELD score. When considering hyponatremia, context matters. You really have to ask yourself, is the patient ready for transplant? One, are they ready for transplant and do they have a liver graft to offer? Secondly, very important to consider and evaluate whether or not the patient with hyponatremia has symptoms that are shown here. When considering liver transplant, context is important. So I wanted to walk through a few case scenarios. So consider a 55-year-old woman with cirrhosis from PBC. She has no symptoms in case one. She's listed for transplant with a low score and mild hyponatremia at 127. For this patient, you likely wanna bring her into clinic, evaluate whether or not there's any adjustments in her diuretics. Fluid restriction likely is warranted if you've already performed these interventions and there are no symptoms and liver transplant is not imminent, you could consider no further intervention. However, if the patient has a higher priority for liver transplant with the MELD rising to 23, that hyponatremia could be intervened upon and important to bring the patient into hospital and start that process as early as you can. If that same patient has severe hyponatremia of 118, strongly recommend that patient come into the hospital as soon as possible and work on correcting that hyponatremia. Now, if the patient does not have an opportunity for liver transplant for whatever reason, it is important to recognize that symptoms drive a need for intervention. So that same patient, not a liver transplant candidate, but has symptoms, mild hyponatremia, important to consider bringing that patient at least to clinic, maybe in the hospital for intervention. Severe hyponatremia with symptoms requires hospitalization and intervention. The University of Washington, we'd likely bring that patient at least to the ward, maybe to the ICU and consider hypertonic saline. What you're really trying to avoid is rapid shifts in serum sodium and the devastating neurologic complication of osmotic demyelination syndrome. Osmotic demyelination syndrome is a demonic destruction of astrocytes leading to significant clinical injury, encephalopathy, seizures, dysphagias, dysarthria, ocular motor dysfunction, ataxia, locked-in syndrome, and even death. Patients are at higher risk for this syndrome when they have low phosphorus, low potassium, low cholesterol, hypoglycemia, and malnutrition. Shown here on the right at the bottom is a classic finding seen on a T2 MRI of a trident appearance occurring in the central pons. Now, ODS in general is uncommon going into transplant as shown by this study of 2,400 patients at four high-volume liver transplant centers. In this study period, before the implementation of meld sodium, there was a low rate of ODS occurring only 0.5% in this cohort. Importantly, however, the ODS was more common in patients who had severe hyponatremia at the time of transplant, particularly those with sodiums under 120. ODS occurred at 8.3% in this cohort with severe hyponatremia. Importantly, there was also increased hospitalization length and days in the ICU. Hyponatremia with a cutoff of 130 is still important, so this is mild hyponatremia. And with that mild hyponatremia going into liver transplant, there's an increase in neurologic complications that's been observed in the 30 days after liver transplant, as well as prolonged alterations in mental status. So what to do with hyponatremia? Well, hopefully I've convinced you that hyponatremia is worthy of attention and often requires treatment. Hyponatremia is a clinically significant complication of cirrhosis. Independent of transplant, its correction can improve quality of life, can improve hepatic encephalopathy, and as I pointed out to you, may reduce the neurologic complications after liver transplantation. Management for hyponatremia first begins with fluid restriction. As many of you know, this is difficult to implement due to poor patient tolerance. It's just hard to restrict the fluid intake to the levels that really make a difference, which is one to 1.5 liters per day. It's important to stop the diuretics, be prepared for increased fluid in that circumstance, correct serum potassium, consider administering IV albumin. This does work, but can be impractical on the long-term. Consider pharmacological therapy, particularly octreotide and mitadrine. It's important to realize that although a V2 receptor antagonist are used and described in the circumstance, they have a black box warning by the FDA in the use of patients with cirrhosis and should be used only for short-curse. If a liver graft offer is imminent, consider the use of hypertonic saline and consider dialysis with a low-sodium dialysate. Shown here is a algorithm presented in a nice review by Dr. Michael Weiss and Andreas Cardenas in liver transplant in 2018. There's some black boxes with modifications after review by our team. Importantly, if the liver graft is not quite imminent, but you're expecting liver transplantation within seven days, you have a little bit more time and wiggle room. You use on the left-hand panel here of octreotide, mitadrine, and IV albumin after stopping the diuretics and free rod restriction can often get that sodium up a bit to over 125 and then it's okay shape probably going into the liver transplant. If you do notice that there's interoperative changes, you can correct overcorrection with D5W or desmopressin. But you do need to monitor that sodium closely interoperatively. Again, if you have a little bit of time up to seven days, you have a sodium under 120, you have some time, you stop the diuretics, you free water restrict, consider intravenous albumin. We also would consider mitadrine and octreotide. If you recheck and you have a sodium that's still under 120, I'd consider use of hypertonic saline, either two or 3%. If you can't get that serum sodium over 120, I'd recommend a multidisciplinary huddle to consider delay or cancellation of the transplant. Now the stakes are a bit higher if you have only 24 hours going into the liver transplant. Again, the interventions are similar. Stop the diuretics, free water restrict, consider intravenous albumin and work to get that sodium over 120. If you can't do that in a fairly urgent fashion, I would consider introducing hypertonic saline at 2% on the ward, 3% in the ICU and to try and get that sodium over 120. This algorithm does include the use of CBVHT with low sodium dialysates. I do wanna draw your attention that standard dialysates will get down to 130 sodium bath. And if you have a sodium less than 120, you have a bath of 130, you're going to exceed that eight point threshold and you put yourself at risk for the sequelae of ODS. So it may be that you need to have special dialysates that are either spiked or concurrent D5W. Now ASLD has made guidance documents here and you can see some of the recommendations that are outlined. The full document is available online, but important that these bullet points show the mild hyponatremia with out symptoms may not require specific management apart from monitoring or free water restriction. Now, if you have moderate hyponatremia, so that's 120 to 125, free water restriction and cystic diuretics are recommended and with more severe hyponatremia, hyponatremia to implement more severe fluid restriction and consider intravenous albumin. The use of vasopressin receptor antagonists should be used with extreme caution given the FDA black box warning and if used, use only in short-term for less than 30 days. Hypertonic saline is reserved for short-term treatment of symptomatic or severe hyponatremic patients or those with imminent liver transplantation. Correction of hyponatremia, when it is chronic, the goal rate of increase should be four to six milliequivalents per liter in a 24-hour period, not to exceed eight milliequivalents per liter in the 24-hour period to ameliorate the risk of ODS. Severe hyponatremia at the time of liver transplant offer, it puts the patient at risk for ODS and the recommendation is for a multidisciplinary coordinated care and considering that liver transplant as a go-no-go. So hyponatremia in the context of liver transplantation, you have to assess whether or not that patient is ready for liver transplant. Do they have symptoms? Hope I've convinced you that serum sodium is not just a number, there are some significant prognostic components of hyponatremia. Its presence is informative in terms of risk for infections and other sequelae of portal hypertension. Hyponatremia can be symptomatic and its correction can improve those symptoms. There are several interventions that I've highlighted and are listed here. Importantly, when you have a go-no-go situation for liver transplant, it's important to assess the severity of the hyponatremia, the urgency for liver transplantation and your institutional expertise in addressing this. Do wanna thank several collaborators that has helped me with this presentation providing data, reviewing the slides and general context of being experts in the field of hepatology and portal hypertension. I'd like to also thank you for your attention and the course organizers for the opportunity to participate in this course. Thank you very much. Hello, everyone. I'm delighted to be here today and to present on this topic. I would like to thank the organizers for inviting me to speak. My name is Anna Konvalinka and I'm a transplant nephrologist and clinician scientist from the University Health Network in Toronto. I have nothing to declare and here are my objectives. I will first start by describing the incidence of chronic kidney disease post liver transplant. So kidney function is often abnormal prior to liver transplant. Unfortunately, serum creatinine is problematic as a marker of kidney function in patients with end stage organ disease. There's several reasons for that including decreased creatinine production in cirrhosis or decreased muscle mass due to malnutrition. Furthermore, effects of end organ disease or treatment may affect kidney function or renal blood flow. And such examples include hepatorenal syndrome, diuretics, ACE inhibitors or ARBs and nephrotoxic antibiotics. MDRD and CKD epi equations are felt to be superior compared to creatinine alone or other equations in predicting kidney function or estimating kidney function but they're not perfect either. Acute kidney injury is very common amongst liver transplant patients, deadly and leads to chronic kidney disease or CKD. So in this article, Oryardan and colleagues reviewed over 300 liver transplants and identified patients who had acute kidney injury defined as two times increasing creatinine or acute kidney failure defined as three times increasing creatinine or dialysis. They assessed patient outcomes at one month and one year. And their first finding was that acute kidney injury and acute kidney failure were quite common. Accounting for 11% and 26% respectively of liver transplants. And in their multivariate analysis, they found that acute renal failure was an independent predictor of 30 day patient survival and also one year patient survival. What about chronic kidney disease? Chronic kidney disease is also common after transplant. And if we look at this image from Ojo et al publication in 2003, we can see for all the different non-renal solid organ transplant, liver is one of the most common transplants associated with chronic kidney disease. And the incidence of chronic kidney disease increases over time, reaching about 25 to 30% after 10 years post transplant. And in our own program, and this is slightly older data from our database Otter, 43% of liver transplant recipients have significantly impaired kidney function as defined by EGFR less than 60 mils per minute. So what are the risk factors of this CKD and chronic kidney disease in liver transplant recipients? Well, the most recognized ones include pre-transplant glomerulofiltration rate, post-operative acute kidney injury, pre-transplant dialysis, use of calcineurin inhibitor, particularly cyclosporine, more so than tacrolimus, hepatitis C, not surprisingly hypertension and diabetes mellitus, and finally year of transplant. So I will now switch gears and tell you about the common causes of CKD in non-renal solid organ transplants. Here are some of the most common causes of chronic kidney disease post liver transplant, and they're in the order of a decreasing frequency. So the most common ones include calcineurin inhibitor nephrotoxicity, prior acute kidney injury or acute tubular necrosis, pre or post transplant hypertension and diabetes, atherosclerotic disease, and then less likely primary or secondary glomerulonephritis, thrombotic microangiopathy, and poliomavirus nephropathy. And so if we think about nephrotoxicity of calcineurin inhibitors, they can cause acute and chronic problems. In the acute setting, they cause a reversible decrease in glomerulofiltration rate by causing vasoconstriction of the afferent arterioles in the glomeruli. But they can also cause chronic progressive or non-progressive decrease in glomerulofiltration rate, which is manifested by hypertension, typically a bland urine sediment without significant proteinuria, and on biopsy histopathological findings that are largely non-specific and showing interstitial fibrosis and tubular atrophy or arteriole hyaluronosis. And very rarely calcineurin inhibitor toxicity can present as acute or chronic thrombotic microangiopathy. And so this is an image of glomerular capillary tuft with the afferent arteriole. And in the presence of calcineurin inhibitor, you can see that this afferent arteriole becomes vasoconstricted. So this study from over 10 years ago illustrated the kidney biopsy findings after liver transplant. They evaluated 81 patients who had mean EGFR of 38 mils per minute, and they had a substantial degree of proteinuria. And most of the findings were non-specific, showing tubular interstitial abnormalities such as interstitial fibrosis and tubular atrophy. But there were also lots of different glomerular findings. And amongst the more specific glomerular lesions, 17% had a specific underlying glomerular nephritis such as membranous or membranoproliferative. But I'd like to point out as well in this table that a lot of patients had increased mesangial matrix, glomerular basement membrane thickness, and glomerular nodular expansion, which are all findings in keeping with diabetic nephropathy. So let me now discuss with you what to do when faced with a liver transplant patient with chronic kidney disease, and some of the findings from randomized control trials of newer agents. There's some universal measures that have been linked to slowing down progression of chronic kidney disease, and they include blood pressure control, renin-angiotensin system inhibitors, particularly in patients who are proteinuric, glycemic control in diabetic patients, low protein diet in patients who have significant proteinuria, treatment of acidosis, and smoking cessation. You will be familiar with some of the immunosuppressive strategies to preserve renal function, which include calcium inhibitor delayed introduction, substitution, reduction, or avoidance. And these studies have not really been convincing in terms of improving outcomes because they're all associated with increased acute rejection or other side effects. But what about novel agents? And this field is really becoming exciting in the last, I would say, five to six years, first with the advent of SGLT2 inhibitors. So what are these agents? Well, SGLT2 inhibitors target a sodium glucose co-transporter in the proximal tubule, and were initially envisioned as treatment for type 2 diabetes for elevated blood sugar. And indeed, they cause glycosuria by blocking reabsorption of glucose and decrease in hemoglobin A1c. Also by failing to reabsorb glucose, they cause a negative caloric balance leading to weight loss. But some of the more interesting and not so anticipated effects include natriuresis. So inhibiting this channel inhibits sodium reabsorption, which results in increased tubular glomerular feedback. So when sodium is not reabsorbed approximately, an increased concentration of sodium is delivered to the macula densa. Since there, adenosine is released and results in afferent arterial constriction, which decreases intraglomerular hypertension and decreases hyperfiltration, which is thought to be the early abnormality in diabetic kidney disease. Similarly, by causing natriuresis, these agents can reduce plasma volume and they decrease myocardial stretch and lead to release of the favorable peptide in the renin-angiotensin system, which is ANT1-7. And I'm sure that in the years to come, we'll continue to discover mechanistic reasons behind the favorable effects of these agents. But really in the kidney world, this SGLT2 inhibitors really came in the forefront with this publication in New England Journal of Medicine in 2016, and this was the MPAR-REG outcome trial. The authors recruited over 4,600 patients with type 2 diabetes who were randomized to empagliflozin and over 2,000 patients that were randomized to placebo. And all these patients had to be on standard therapy, including other RASPs inhibitors. Their mean age was over 60. They were mostly male. They were obese. They had two groups of patients, a group with EGFR that was less than 60 mils per minute, and a group that was greater than 60 mils per minute. More than half of the patients in the low EGFR group had proteinuria, and about a third of patients in the high EGFR group had macroscopic proteinuria. And some of the pre-specified, this trial, the primary endpoint was cardiovascular, but some of the pre-specified endpoints included progression to macroalbuminuria or doubling of serum creatinine level, defined as progression of diabetic nephropathy, initiation of renal replacement therapy or death from renal disease, and incident albuminuria. And when we examine this initial worsening nephropathy, empagliflozin was superior to placebo with a hazard ratio of 0.61, in a very narrow confidence interval, and this was very strongly significant. And when we eliminate the cardiovascular endpoints, the post-hoc renal composite outcome was, showed that empagliflozin was even more superior, decreasing probability of renal events by almost 50%, with, again, a narrow confidence interval. And they used two different doses of empagliflozin, 10 milligrams or 25 milligrams. And if we look at the adjusted mean EGFR in these patients, you can see that in the first month after treatment, empagliflozin resulted in a decrease in EGFR, and that could have been predicted from the knowledge of vasoconstriction of the afferent arteriole in the glomeruli. However, EGFR then subsequently recovered and stayed reasonably stable over the subsequent weeks of follow-up in contrast to placebo. And when we look at all the renal outcome measures, you can see that empagliflozin was superior for all of these renal outcome measures apart from incidental pulmonary neuronea. And so this study really suggested that in patients with type 2 diabetes, at significant risk of progression of chronic kidney disease, empagliflozin was effective in significantly reducing CKD progression, but added to standard of care. So the subsequent trial, Credence trial, which was published again in New England Journal of Medicine in 2019, examined its primary composite outcome renal outcomes. And here they recruited again over 4,000 patients with type 2 diabetes and chronic kidney disease. And these patients had a mean EGFR slightly higher than those from EMPIREG trial at 56 mils per minute and had a high degree or moderately high degree of proteinuria with 93 milligrams per millimole. Again, they were similarly aged, mostly men hypertensive with longstanding type 2 diabetes. Their primary composite outcome was end-stage kidney disease, doubling of serum creatinine or renal or cardiovascular death. And when they took all these, this primary composite outcome into account, conagliflozin was superior compared to placebo, but a hazard ratio of 0.7. And when cardiovascular death was excluded and only renal specific composite outcome was taken into account, hazard ratio was around 0.66. Again, very similar to what was seen in the EMPIREG trial and conagliflozin was again superior. And again, looking at the different subgroup analysis, you can see that across the range of EGFRs, conagliflozin was superior compared to placebo. And this effect was the strongest with EGFR less than 60 mils per minute. This effect was also stronger in patients who were proteinuric, although the number of patients who had lower grades of proteinuria was lower in this and in all other trials of these agents. So this suggested that conagliflozin was also effective in reducing renal outcomes and that it may be effective in slowing down progression of proteinuric patients with CKD and type 2 diabetes who are already on standard of care therapies. But what about patients who have chronic kidney disease that is not due to type 2 diabetes? And this was the theme of DAPA CKD trial, which was published last year in New England Journal of Medicine, which recruited over 4,000 patients with EGFR roughly between 25 and 75 mils per minute who were randomized to DAPA conagliflozin or placebo. And again, this trial recruited very similar population of patients with the previous SGLT2 inhibitor trials, but keeping in mind that two thirds of patients had type 2 diabetes and a third did not have diabetes. So this was a CKD stage three with moderate degrees of proteinuria. All patients were on standard of care therapy, including RAS inhibitors. And the primary outcome was the composite of a sustained decline EGFR of at least 50% in stage kidney disease or death from renal or cardiovascular cause. So very similar primary outcomes to the previous ones. When we look at the primary composite outcomes, again, hazard ratio was almost identical to the previous one with DAPA conagliflozin being superior to placebo. And when we looked at renal specific outcomes, again, DAPA conagliflozin had an even better hazard ratio of 0.56. Similar to empagliflozin, DAPA conagliflozin resulted in an initial decline in EGFR followed by stabilization. And when we look at the different subgroup analysis, actually all of the groups seem to benefit from DAPA conagliflozin. And if we look at the patients who had type 2 diabetes or those who did not, we can see that both groups had a significant benefit from DAPA conagliflozin. So this suggested that SGLT2 inhibitors may be effective in slowing down chronic kidney disease progression, even in patients with non-diabetic chronic kidney disease. What are some of the other agents? Well, another group of promising agents is non-steroidal mineralocorticoid receptor antagonists. And one such selective antagonist that has a short half-life is finaranone. So finaranone has both direct hemodynamic effects and also some indirect effects that target mineralocorticoid receptors in parenchymal tubular cells. What has been observed is similar to SGLT2 inhibitors, early decrease in EGFR, pardon me, followed by stabilization. And these agents also seem to decrease intraglomerular hypertension and seem to decrease inflammation by directly targeting the adverse pro-fibrotic signaling pathways of mineralocorticoids in tubular cells. And the first trial published in 2020 in New England Journal of Medicine that directly addressed renal outcomes was the FIDELIO-DKB trial, which recruited over 5,700 patients with CKD and type 2 diabetes. And similar to the previous trials, these patients were 65 years old, mostly male and hypertensive. And similarly, their EGFR and proteinuria were very similar and comparable to those patients recruited to SGLT2 trials. Primary outcome was composite of end-stage kidney disease, decline in EGFR, or death from our renal cords. And when we look at the primary composite outcome, finaranone was superior to placebo with a hazard ratio of 0.82, and you can see the confidence interval. So not as impressive an effect as SGLT2 inhibitors. And most of this effect was really driven by decline in proteinuria, as you can see here, by significant decline within four months of randomization in the finaranone group. When looking at the individual outcomes, you can see there was a trend towards an improvement in finaranone for most of these outcomes, including some of the renal outcomes. However, one of the problems that had not been seen with SGLT2 inhibitors, and that was really anticipated with this type of medication, was hyperkalemia, and this was more common in the finaranone group. So the second trial then came out, FIGARO-DKD, just published a few months ago in the New England Journal of Medicine, which recruited over 7,000 patients. Again, very similar population of patients with CKD and type 2 diabetes, mostly with cardiovascular disease, mostly male, but this time had lower, sorry, higher EGFR, and had lower proteinuria compared to the other patients. They had to have normal potassium levels in order to be recruited. They all were on standard of care, and interestingly, 16% were actually on SGLT2 inhibitor or GLP-1 receptor agonists. And you can see the primary endpoint was cardiovascular while the secondary endpoints were renal. And when we look at the primary composite outcome, finaranone was superior to placebo with a Hazard Ratio of 0.87, and most of the benefit was driven by the lower incidence of hospitalizations for heart failure. When we look at all the outcomes independently, again, there was a trend for finaranone being better, and you can see the renal composite outcomes, which largely crossed the line of one, but tended to favor finaranone. There was some incidence of severe hyperkalemia, and this was more common in the finaranone group. Finally, Fidelity came out, which was a pooled analysis of these first two trials and confirmed this favorable effect in reducing proteinuria and even in reducing end-stage kidney disease by 20%, which was significant. So it's felt that this agent is complementary to ACE inhibitors and ARBs as well as to SGLT2 inhibitor. And finally, GLP-1 receptor agonists are a new group of agents that are very interesting in that they are released by intestinal cells and tend to slow down gastric motility and to increase insulin release. However, they had some favorable and previously unpredicted effects on the kidney, and preclinical studies demonstrated decreased oxidative stress due to decreased NADPH oxidase, increased natriuresis due to inhibition of the sodium hydrogen exchanger in the proximal tubule, decreased inflammation, and consequently, they're thought to be able to decrease renal fibrosis and to protect the kidney. Well, here's the list of big randomized control trials with these agents. Renal outcomes were not primary outcomes in any of these trials, but secondary outcomes. And all the trials actually showed favorable effects for the kidney with these hazard ratios, but most of the favorable results were driven by reduction in proteinuria and not by stabilization of EGFR. These agents are not approved for EGFR less than 30 mils per minute. So to conclude, acute and chronic kidney disease is common before and after liver transplant and carries increased morbidity and mortality. Calcineurin inhibitor nephrotoxicity is an important cause of chronic kidney disease, but its features on the biopsy are nonspecific. There are new and exciting agents that have emerged, particularly for type two diabetes and chronic kidney disease with moderate to severe proteinuria. And FGLD2 inhibitors are effective at decreasing renal outcomes and are becoming the therapy of choice after standard of care has been given to the patients with chronic kidney disease. With that, I will thank, I will credit my colleague, Dr. Geoffrey Schiff, who assisted me with some of the earlier slides. And I'll be happy to answer any questions. Good morning, ladies and gentlemen. My name is Annalisa Perfigotti from Bern in Switzerland. And I would like first of all to thank the organizer for inviting me being here today. It's a big honor. And my task today is to go through the pharmacotherapy for weight loss in cirrhosis and liver transplantation, which I think you will agree, it's a bit of forgotten approach. This is my disclosure. And this is the outline of my talk. I would like to start framing a bit the problem and telling you about obesity in cirrhosis and after liver transplantation and its impact. So it's important to know that obesity is a frequent problem or a frequent comorbidity in patient with cirrhosis. In compensated patients with advanced liver disease and in compensated cirrhosis with portal hypertension, it has been estimated that between 30 and 40%, according to the different population and irrespective of the etiology. In addition, of course, we are all aware that NASH cirrhosis is increasing and it's becoming the most frequent cause of liver transplantation. And why obesity is important in compensated patient with cirrhosis? Because it adds to the risk to develop a first decompensation. You can see from this study, which was conducted in patient with a portal hypertension, no viruses, included in the Timolo study published some years ago, that being obese meant to have a three time higher risk of developing a first decompensation independent of albumin and HVPG. And in addition, patients with obesity had a higher HVPG increase over the years as compared to patients in overweight or obese or normal weight. Therefore, it's a risk factor for the compensation. But also in decompensated patients, obesity increases some of the risks. And an important risk we all know that worsens mortality in decompensated patients are bacterial infection. And you can see in this very large nationwide inpatient study in the US that patients with obesity in general, but even more in obesity class three, so over 40 milligrams per square meter body mass index had a higher rate of infections. In addition, there are already some reports stating that obesity per se in patients awaiting liver transplantation is a risk factor for portal vein thrombosis. And we are all aware that this complicates the surgical part of a liver transplantation. Furthermore, it's important to remember that obesity is a major risk factor for the development of hepatocellular carcinoma. And then it adds risk by acting on a mechanism leading to HCC different from that of many etiologies of liver disease. So summarizing this part of my talk, I would like to say that obesity adds risk or induces progression to the liver disease in each step of the natural history of chronic liver disease. And there is already some record also stating that it prevents regression of fibrosis. So this is an important and modifiable risk factor, whatever the etiology of liver disease is. And NASH, which is becoming the most common indication for liver transplantation is closely associated with obesity and other components of metabolic syndrome. And it is becoming increasingly clear that grade three obesity can be a problem in the post liver transplant setting. It can prevent liver transplant eligibility in several of the centers. And we will enter a bit more in detail on the data on these points. This is a larger systematic review and meta-analysis published regarding the impact on patient and graft survival of obesity in patients undergoing liver transplantation. And you can see that obesity per se and even more obesity of at least grade two is associated with overall reduction in survival rate and overall reduction of graft survival as compared to patient normal weight. In addition, patients who are obese or at least overweight will have an increased risk of new onset diabetes after liver transplantation. And there is already also some report that patients obese on the weight release of transplantation have an increased dropout and mortality rate. So can we take action apart from the well-known lifestyle changes that we all try to apply? What can we do? What pharmacological therapy could be used in patients with cirrhosis and in the setting of post liver transplantation? So I will just touch very shortly on the pathophysiology of obesity and we will go through the available drugs. It's so complex, the pathophysiology of obesity that it's impossible to go through it in a short time. What seems very important to know is that of course everything starts with an excess of calorie intake and energy intake let's say as compared to energy expenditure but the different organs and mechanisms included are highly and complexly interregulated and there is a large part of the process regulating all the pathophysiology of obesity that is centrally regulated. So in the brain happens most of what we observe in terms of onset and maintenance of obesity. So let's see where and how the existing drugs act to promote weight loss. There are drugs acting centrally. So in the brain mechanism and they promote society and inhibit appetite. There are drugs that reduce fat absorption in the intestine. There are drugs able to regulate glucose concentration and insulin sensitivity or induce urinary loss of glucose and drugs that lower the gastric intake. We will see them one by one. Let's take the easy one which is quite simple to understand. So reduction of intestinal absorption of triglyceride mediated by Orlistat which is a reversible inhibitor of gastric and pancreatic lipase and acts then by blocking the absorption of the triglyceride is able to induce weight loss and it is approved by the FDA and EMA. The pros in the pre-liver transplant setting is that there is some data on positive effects of Lanshan we will see and it seems not to be needed to adjust its dosage in patients in advanced stage of liver failure. The cons are that it is frequently associated with nausea, abdominal cramps, fecal urgency, and there are some cases of DILI documented on it. It has an interference with vitamins absorption, and also it's possible to have some interference with the absorption of some drugs. And in the post-liver transplant setting, there is a documented interaction on the decrease of calcineurin inhibitor. This is a meta-analysis showing in the general population what you achieve using Orlistat in obese patients. You see that there is a definite weight loss, but it's quite a moderate weight loss. And in patients with NASH, it has been proven that NASH improves in patients on Orlistat. So there is a decrease in steatosis, a decrease in ballooning and inflammation, which is significant, but there is no change in liver fibrosis. Then we enter into the much more complex setting of drugs with central mechanisms. I will, of course, not enter into the molecules that are mediating these effects, but it's important to know that this whole group of drugs act in the brain, promoting society and inhibiting appetite. Among them, phentermine and topiramate, which are respectively asympathic-mimetic and anti-epileptic, anti-migraine drugs are used in combination for obtaining a weight loss. And when they are combined, their respective side effects are reduced. And these are drugs that have been approved by FDA, but rejected by EMA. There are no studies in liver disease why there is a suggested dose reduction in type 2B and avoid the use in type 2C. And some of the side effects are dry mouth, constipation, insomnia and paresthesia. They are contraindicated in patients with medical history of drug abuse, and it is not really very well known if there is an interaction specifically to the immune suppression. Similarly, naltrexone, which is a competitive antagonist of opioid receptor and bupropion, which is an antidepressant, are used in combination and approved by the FDA and EMA to promote weight loss. Again, exactly as with the other drugs, there is no study specific in liver disease. And similar to before, they are contraindicated in patients with medical history of drug abuse and also in patients with seizure history. Coming to a more modern or more recent group of drugs, which were not initially designed to treat obesity, glucagon-like peptide 1, so GLP-1 analogues, are an interesting group of drugs that increase glucose-dependent insulin secretion, decrease inappropriate glucagon secretion, slow gastric emptying, and also, with central effects, they reduce appetite. There are already several molecules on the market as antidiabetic drugs, but only lyraglutide has been approved for the treatment of obesity by the FDA and by EMA. There are no trials in cirrhosis yet on these drugs, but there are some upcoming. And however, it is considered safe in patients with advanced liver disease and definitely beneficial in menstruation. We will see it in a moment. Their major cons are nausea and diarrhea, and if used in patients with diabetes, some special care has to be taken, but I will not enter in detail on this. In the post-liver transplant setting, there are several reports reporting cardioprotective effects, improvement of diabetes, similar to what happens in non-transplanted patients, and potentially, they then reduce the recurrence of NASH. They don't seem to interact with immune suppress. This is the key randomized control trial that has been published in Lancet in 2016 by Armstrong and colleagues, where lyraglutide met the primary endpoint of histological reduction of NASH with no worsening of fibrosis and showed a clear reduction in body weight and improvement in metabolic syndrome. If we look in the general population, because it's where we have data, general population with obesity, what is the efficacy of these drugs on weight loss? And compared to the risk of side effects, we see that Orlistat is associated with not a very high effect on body weight, but also not high effect adverse events. Drugs acting centrally have a higher efficacy, but also higher risk of adverse event, and lyraglutide is a drug associated with very high efficacy and acceptable risk of side effects, which are mostly well manageable. There are other drugs that have been more recently introduced, not yet approved for the use in obesity, but approved as anti-diabetic agents. These are sodium glucose co-transported protein inhibitors, SGLT2, and more recently, SGLT1, or dual action. These are drugs that mediate excretion of glucose from the kidney, and with another mechanism, they also mediate intestinal absorption of simple sugars. They are being tested in NASH, and in the pre-liver transplant setting, they might be beneficial in patients with NASH, with high cardiovascular risk, and they might even improve the treatment of ascites, even if there is a high risk of concern of genitourinary infections, both in the pre-liver transplant setting and in the post-liver transplant setting. This is some data recently published in a patient with obesity on glycoglycosine, which is one of these dual inhibitors of SGLT1, and two, and you can see that weight reduction effect was modest, even if significant. It's interesting, however, to know that they have been tested under investigation, say, in NASH, and there is a positive effect not only on body weight, but also on ALT and GGT, and the histological results of these drugs will be seen in the future studies, and with the final results of these trials. Some algorithms have been proposed for the management of obesity in cirrhosis, and you can see that there are limitations on whether we would use pharmacological therapy. First of all, there must be a question on whether a patient could be a candidate to liver transplantation. A patient with decompensated cirrhosis candidate to liver transplantation should be assessed whether they have severe protein malnutrition, and if the patient can be accepted for liver transplantation with the current body mass index, and even if the transplant center is able and is experienced in doing simultaneous liver extraction and transplantation, well, if any of these questions can be answered positively, then probably it's better to defer pharmacological treatment and just go to liver transplantation. In case this is not the case and the patient is not in one of these conditions, then there could be a choice of treating patients with one of the drugs that we just assessed. Kidney insufficiency is a major issue, and many of these drugs cannot be used without a dose reduction in patients with kidney injury, and in this sense, likely lyraglutide or GLP-1-analogues are the drug of choice in these patients, and also for the safety in advanced liver disease, likely CHI-PUC-C patients can be treated with either Ornistat or lyraglutide. In patients in the setting of post-liver transplantation, again, we should consider whether there is end-stage kidney disease or not, and what are the comorbidities that could be problematic when using one of these drugs, and again, probably lyraglutide and Ornistat can be used in most of the situations. As future perspective, this is just a word because we don't have data yet, but there is an exciting new group of targets that are being discovered, and these are what is called exercise mimetics. As you all know, physical exercise has a series of very positive effects that go beyond weight loss, and there is now, they have been discovered some different possible targets that mimic the effect of exercise, and interestingly, in a very recent paper in Nature Metabolism of this year, it has been shown that exercise therapy triggers anti-inflammatory trained immunity of Kupfer cells, and the mechanism mediating this has been discovered, so now we know which cellular and molecular targets are the triggers of the positive effects of exercise on immunity, and this could be really a game changer because if we can create a drug mimicking this action, then we would probably have a completely new tool or new drug to use in our patients complementary to those one existing. My take on messages are that obesity is a major modifiable factor impacting the progression, prognosis, and treatment options in cirrhosis, that pharmacological treatment of obesity is possible in this situation, and some of the options show encouraging results in patients with NASH and solid organ transplant recipients. This pharmacotherapy should be integrated in the management of obesity in cirrhosis and in the post-liver transplant setting, and who knows, but I do hope that exercise mimetics could represent a promising therapeutic option for obesity in the future, and I would like to thank the ASOD Governing Board and the course organizer for inviting me. I would like to thank all my group, but in particular Dr. Chiara Becchetti, who is indicated with the blue arrow in this picture of a happy group of colleagues. She was key for the preparation of this presentation, and I would like to thank my former head, Professor Jean-Francois Dufour and Jaime Bosque for helping me during all these years of my career. Thank you for your attention. Thank you, Chair. First of all, I want to thank the organizing committee for inviting me, and I have nothing to disclose. Well, I work at the University Hospital of Pisa in Italy, where a liver transplant center was established in 1996, and at that time, the recommended approach to recovery after liver transplantation was represented by a slow and smooth transition from surgery into the postoperative period, and to this end, we used quite liberally opioids and benzodiazepines, and we kept our patients mechanically ventilated even until the next day to provide the best possible support in a period where many and different causes could even seriously jeopardize patients' tissues, oxygenation. However, in 1997, for the first time, the concept of fast track was introduced to organ transplantation as a process of care aiming at the rapid progress throughout the procedure, emphasizing an efficient use of available resources, and as anesthesiologists, we were called to facilitate this process using short-acting medications and fluid-restrictive approach during surgery and early extubation techniques, and in the same year, that's 1997, it was published the first study to use a systematic approach to early recovery in this class of patients, and as you can see, about the 24 percent of the enrolled patients were extubated earlier than usual practice without major complications or outcome differences when they were compared to other patients who were treated according to a traditional protocol. Also, some cost saving was shown mainly due to less ICU stay. In this study, it is interesting to see that although it was carried out at two different centers, that's University of Colorado and UCSF, where two different definitions of early extubation were used, the same factors precluding it resulted. That's a poor graft function, the presence of encephalopathy before surgery, and the need for a large amount of transfusions during surgery. As I told you before, in PISA, we started our liver transplant activity in 1996. That's one year before the publication of the study, and I have to say that as newbies to the procedure, we were very impressed with its results. However, I have also to admit that we felt rather skeptical because we thought that the few and minor adverse events which were outlined in the study were due to the fact that the enrolled population was very highly selected and so rather healthy. And so we wanted to see if an early extubation could be possible and safe, even in patients with clinical characteristics that did not necessarily predict the best outcomes. And so after a quick pilot study, we started a prospective one where we enrolled 181 consecutive patients without using any predetermined criteria to enroll them. We used the same anesthetic protocol and we recovered them from anesthesia in the ICU and so in a friendly and safe environment as soon as possible using the extubation criteria that any anesthesiologist uses all around the world at the end of surgery. And as you can see, we were able to extubate more than the three quarters of our study population within eight hours from the end of surgery, 63 percent of them within three hours in a time where when postoperative mechanical ventilation, even when it was not clinically needed, was the standard of care. The procedure was quite safe. In fact, only nine patients were re-intubated, mainly due to surgical problems and the severity of the liver disease, which at that time was classified according to the child pool classification, did not influence early recovery. This study was published one year later and it is very important because for the first time and immediate after surgery, tracheal extubation is reported. It was performed in the 75 percent of the patients, 56 percent of them were then discharged to the surgical world after a quick stay in the postoperative care unit and so without any stay in the ICU. And again, the severity of the end-stage liver disease had little or no influence on the extubation success, whereas encephalopathy and significant bleeding predicted prolonged intubation. We further confirmed these findings a couple of years later in a population of more than 360 unselected patients. We were able to extubate about 60 percent of them immediately at the end of surgery in the OR. And again, transfusions were associated with prolonged intubation, whereas the severity of the liver disease did not preclude it. This is the only multi-center study which is available so far. It was performed at seven centers in the US and Europe and it is interesting to see that although the same criteria indicating tracheal extubation, the same definition of it and the same anesthetic protocol were used at all the participating centers, some significant performance differences between the institutions were shown in the number and severity of the peripheral adverse events, meaning that center-specific practices and differences will play a role in a successful early tracheal extubation in liver transplant patients. So the message here is if you are considering to start an early recovery protocol at your center, remember that the predictors that you can read in the literature may not be the same at your own site. And finally, I want to show this study from Mayo Jacksonville which is very important for two reasons. The first is that it is based on a huge database of around 1,300 patients. They were successfully and safely extubated in the 54 percent of the cases in the OR and then discharged to the surgical ward, so bypassing the ICU. And the second reason is that this database was used to build a probability score to predict the successful allocation of care after the procedure. And this score was internally validated in this same study. But many other studies have been published from almost any country where liver transplantation is performed, all of them confirming the feasibility and safety of early extubation after liver transplantation, including this meta-analysis of more than 4,100 patients, showing that those who were managed according to an enhanced recovery protocol required less reintubation after surgery, suffered less complications, and stayed less in the hospital. However, early recovery practices in liver transplant patients do not seem to be universally accepted yet, and there is still a significant debate whether this practice serves patients' best interest, especially in everyday clinical practice and so outside study conditions. And at present, in most centers, at the end of surgery, patients are discharged, still intubated in the ICU, where a period of protocolized postoperative mechanical ventilation is given, with a large variation between the single institutions in the way these patients are managed after surgery. But why so? Well, for many, trichal extubation after liver transplantation is of little value, because it is true that we do not have unanimous data yet about less ICU stay and costs when it is adopted. Moreover, we are still waiting for clear quality measures of process and outcome when early trichal extubation is performed. Furthermore, the introduction of the MELD score to prioritize candidates to liver transplantation changes globally their clinical picture, so that now they can look to will for being weaned earlier from anesthetics and then extubated and then even bypass the ICU, justifying some possible doubts about the real risks-to-benefits ratio of the procedure and also an indecision about the convenience of being engaged in a new learning curve, because, indeed, this practice challenges usual care practice. So, in summary, the concept itself of fast track, as it was proposed in 1997, nowadays seems pretty weak, because it results as a generic term that describes a plan of care that is simply accelerated by the application of isolated steps of care earlier than usual, where patients may lack enough care to facilitate safety of these early interventions. In other words, there is nothing that seems to bind together all the different steps of care. In contrast, the more modern concept of ERAS seems more attractive, because it is a multimodal perioperative care pathway, which is designed to achieve early recovery for patients undergoing complicated surgery. And where every step of care is integrated with the others and all together are aimed at a common target that's improving the flow of care into surgery. However, we also know that an EROS protocol includes the application of several different steps of care and intervention, raising the question whether this will be sustainable in an already complex and complicated clinical scenario like that of the perioperative liver transplant patient. And from this point of view, we do not have much evidence. For example, we have the study from China where a 13 points EROS-oriented protocol was used in 54 patients. And as you can see, they stayed less in the ICU and in the hospital with a comparable complications rate when they were compared to other 74 patients who were treated according to a traditional protocol. We have also this pilot study from France using a very detailed, a more detail-rich EROS protocol, including 26 items. And again, patients in the EROS arm stayed less in the ICU and in the ward with a global 47% reduction of their length of stay in the hospital. However, if we look inside the characteristics of these two study populations, we will see an issue. In fact, due to safety concerns, the inclusion and the exclusion criteria for the patients included in the EROS arms were very strict. And in fact, in both the Chinese and the French study, the MEL score of the two populations were around seven. The consequence is that only a few of the patients were or could be considered for an EROS approach for being included in an EROS protocol, if we only look at their MEL score. However, we also should remind that only the need for a continuous renal replacement therapy, the presence of an encephalopathy before surgery, and significant bleeding during it, has been identified so far as reliable indicators precluding early recovery and fast tracking, and not the severity of the liver disease. Moreover, we also know that the MEL score is affected by several limitations. One of them, perhaps the most important, is that it does not take into consideration patients' general health status. And on the other side, we know that there are patients, and they are not a few, with a quite good biological status, but a high MEL score, who could be ideal candidates for being included in an EROS protocol, but who should be missed if we look only at their MEL score. So, it is important that our own clinical judgment and experience will never be forgotten, because they are at least as much important as any score, as it has been outlined in this very recent study from Toronto. And in fact, in this very recent paper from Spain, of more than 230 patients, the mean MEL score was 15, and they were, in all cases but four, extubated immediately after surgery. They stayed a median of 13 hours in the ICU, and a median of four days in the hospital. The key for the successful application of a very detailed EROS protocol, including 28 items, was the creation of a multidisciplinary team, including surgeons, anesthesiologists, hepatologists, critical care physicians, nurses, and so forth, to devise a fast-track pathway, including all the available and proven knowledge in early extubation, short ICU stay, and rapid progress through the surgical world onto discharge. And this pathway was designed specifically for that center. And the importance of teamwork was also emphasized in this very recent expert opinion by Dr. Mandel, who is the pioneer in early tracheal extubation and fast tracking of liver transplant patients. And in fact, Dr. Mandel outlines that the setting of shared goals of care, the use of a continual quality improvement approach under a clear leadership, will encourage all team members to take their own responsibility for the care and outcome of patients included in a very detailed rich EROS protocol. So, coming to my conclusions, liver transplant surgery changes significantly over the years, with better patient selection, larger experience, and improved human skills. The same happened to liver transplant anesthesia. And in fact, nowadays, we have available newer medications and technologies. And most importantly, our knowledge of patient pathophysiology improved significantly. The same also for hepatology, that improved significantly in the preparative medical care of liver transplant patients. Altogether, it made it possible to think that things can be done differently, and perhaps also better than usual. We know from evidence that early postoperative weaning from anesthetics and liberation of the patients from mechanical ventilation is possible, safe, and will accelerate their process of care. However, for too many years, we focus on tracheal extubation as the end of our care, rather than considering it just a tool towards better preparative care. Nowadays, we have available EROS protocols, which are attractive and also prove effective in many areas of surgery. However, they still remain quite not explored in the field of liver transplantation. It is important to be aware that EROS protocols are very detail-rich, and so they require some strategic planning by a dedicated team to be used in a complex scenario like liver transplantation. And from this point of view, the very recently available specific guideline from the EROS Society and the future conclusions from the LTS consensus conference will help much. However, it should be reminded from my personal point of view that the first step belongs to ourselves, the clinicians, because when we consider starting an enhanced protocol of liver transplant patients, we have to consider that we need a new mindset and our personal commitment, because indeed, it will challenge our local and personal beliefs. From the strict anaesthetic point of view, an EROS-oriented preparative care of this kind of patient or this class of patients is very interesting, because it can help towards improving our care performance, safety, and cost-effectiveness, because indeed, it requires to collect and analyze our data, to adopt standards, to talk to our colleagues of other disciplines, and reach with them a consensus about the best preparative protocols. And also, we need a focused team with the leadership. And future clinical trials will help determining how the different steps in a detail-rich EROS protocol can interact with patients' clinical characteristics to influence their outcomes. Thank you very much for your kind attention. Hello, everyone. My name is Amelia Hessheimer. I'm a surgeon currently working in Madrid, Spain. I would like to thank the AASLD and the ILTS for the opportunity to present today and discuss the use of machine perfusion preservation in deceased donor liver transplantation. These are my disclosures. Broadly, deceased donor liver grafts can be categorized between standard quality and substandard quality or marginal grafts. While definitions may vary, in general, standard quality livers arise from relatively young donation after brain death or DBD donors less than 65 years of age, with no or only mild steatosis and a cold ischemia time of less than approximately 8 to 10 hours. While cold storage has for many years remained an adequate form of preservation for the so-called standard quality grafts, one has to keep in mind that it slows graft metabolism, but metabolism never actually ceases. In this regard, dynamic preservation strategies, continuously replenishing substrates and removing waste products have gained increasing traction in recent years. Perfusion strategies are generally classified according to the temperature at which they are performed. As temperature perfusion increases, so too do oxygen requirements. At higher temperatures, subnumerothermic and normothermic, the addition of an oxygen carry to the perfusion solution is necessary. There's also the option of controlled rewarming, whereby temperatures are slowly and progressively raised from hypothermic to normothermic range. The primary forms of machine perfusion preservation that have been applied clinically are hypothermic and normothermic. Hyperthermic perfusion targets graft mitochondria and aims to improve their condition prior to an ability to deal with reperfusion injury. Hyperthermic perfusion is technically easier to perform and does not require the inclusion of a specific oxygen carrier in the perfusion solution. As well, it presents low risk for bacterial and or fungal growth. Normothermic perfusion, on the other hand, aims to recreate physiological conditions for the organ outside the human body. Bile is produced in normothermia and can be analyzed. With the liver fully metabolically active, normothermic machine perfusion offers the best opportunity to assess graft viability and function. That said, it is more technically complex to perform and may actually lead to oxidative stress and reperfusion injury in injured or inappropriately resuscitated grafts. Modern application of liver machine perfusion has been elaborated in a series of clinical pilot studies published over the course of the past decade, evaluating its use in a priori standard quality livers accepted for transplantation regardless of the preservation modality used. Aside from the pivotal study published on hypothermic machine perfusion by James Guerrero in 2010, most have been performed using normothermic machine perfusion as the ex-situ preservation modality. Among these, a now well-known randomized clinical trial on deceased donor livers demonstrated a significant reduction in peak post-transplant aspartate aminotransferase, which was the primary study endpoint. No differences were observed, however, in any major clinical measure of outcome, including survival and biliary complications, but the study was not necessarily powered to detect any of these. In the aforementioned randomized clinical trial, it should be noted that some livers that were initially accepted for transplantation in the normothermic machine perfusion arm were ultimately not transplanted. While reasons vary, this is an important point to keep in mind when considering the use of normothermic machine perfusion, in particular, in standard quality grafts. Given that livers are entirely metabolically active at 35 to 37 degrees Celsius, there is potential to actually provoke warm ischemic injury if delivery of oxygen and other critical substrates is cut off for whatever reason on the ex-situ perfusion device. For the aforementioned reasons, while standard quality deceased donor livers may be important for proof of concept clinical pilot studies, the increased costs and potential for graft loss without any realistic expectations for improvements and results at this point make ex-situ machine perfusion otherwise unpractical and unnecessary in standard quality deceased donor livers. Marginal liver grafts, on the other hand, tend to fare less well with static cold storage. In general, these are grafts arising from donors of advanced age, though good results with older livers have been described, especially when other risk factors are limited. More importantly, there are donors with high BMI, with moderate to severe macrostatosis, and, of course, donation after circulatory determination of death, or DCD, donors. Other additional risk factors for an adverse graft and or patient outcome have been identified, including donor hypernatremia and altered liver function tests, certain causes of death, and risk for transmission of different disease processes. However, the majority of the work on extended criteria donors and perfusing EC livers has been focused on steatotic and DCD grafts. DCD livers used for transplantation are by and large high risk because of the pre-recovery period of warm ischemia they suffer. Warm ischemia leads to anaerobic metabolism, cell acidosis, cell breakdown, and cell death. Warm ischemia is particularly injurious at the level of the biliary tree and the peribiliary plexus, which is considered the Achilles heel in DC liver transplantation due to increased risk for stenotic lesions, which may be progressive and are generally not seen until three to six months after transplantation. These ischemic type biliary lesions or biliary strictures can lead to repeated bouts of cholangitis, development of intrapartic abscesses, and even graft loss or patient death without retransplantation. In order to avoid the development of such adverse outcomes, different risk scores have been developed, such as the UK DCD risk score, which helps to identify and potentially even avoid the transplantation of DCD livers with high risk for graft loss. Based on these known risk factors, experienced groups performing DCD liver transplantation perform meticulous selection in order to avoid adverse post-transplant events. In doing so, while they can largely avoid biliary complications and graft loss, they also limit the applicability of this procedure as a lifesaving option. As you can see in this table, donor age in particular is significantly limited in DC liver transplantation many centers. When donor age is increased, cases of ischemic type biliary lesions and other biliary complications are more frequently observed, as can be seen in the red cells in the table. Macrostatosis is another major determinant of adverse graft outcomes following liver transplantation. This is based on the fact that macrostatotic grafts have impaired mitochondrial function at baseline, leading to increased oxidative stress and inflammatory responses upon reperfusion. In addition, the presence of fat macrovesicles in the hepatocytes reduces sinusoidal diameter and causes microcirculatory disturbances following additional cellular edema arising after graft reperfusion. There are also marginal grafts that combine risk factors. In this recent report, it was seen that while the use of DCD grafts with moderate macrostatosis did not result in worse overall graft survival relative to non-fatty DCD grafts, the incidence of serious perioperative events, including reperfusion cardiac arrest, primary non-function, and kidney failure was significantly greater when moderately statotic DCD grafts were used. Biliary complications were not seen to increase in fatty DCD livers, a reflection of the fact that macrostatosis and warm ischemic injury target different liver cells. Normothermic machine perfusion has also been applied in what has been described as ischemia-free liver transplantation, whereby the NMP device is connected to the liver and the donor, and the liver is removed and maintained under continuous normothermic perfusion until transplantation recipient. Using this technique, the group in Guangzhou, China, has described a number of successful marginal transplants, including using grafts with up to 90% macrostatosis, without observing any of the changes seen with ischemia or perfusion injury in either grafts or recipients. Marginal livers, primarily DCD, have also been perfused clinically, largely using hypothermic machine perfusion, and largely performed with active oxygenation. As can be seen in these case series, even using grafts with extended donor warm ischemia periods, and some with extended cold periods as well, use of ex situ hypothermic machine perfusion is associated with acceptable post-transplantation outcomes, better than those seen with direct cold preservation, and decent results with regard to biliary complications and graft survival. The incidence of biliary complications, in particular ischemic-type biliary lesions or non-asthmatic biliary strictures, was the primary endpoint in this recent fantastic randomized clinical trial led by the group from Groningen in the Netherlands. The dual hypothermic oxygen perfusion or D-HOPE trial demonstrated the use of this preservation modality in controlled DCD livers significantly reduced the rate of ITVL from 18% with direct cold preservation to only 6%. As well, it was seen that among cases developing ITVL in the D-HOPE group, they were more able to successfully treat the cases in fewer sessions of endoscopy or interventional radiology. Another perfusion technique that has gained traction in recent years in the recovery and preservation of DCD livers is that of in-situ normothermic regional perfusion, whereby perfusion of oxygenated blood is restored in the abdomen immediately following warm ischemia without any intervening cold ischemia. Normothermic regional perfusion is capable of reversing deleterious processes arising during warm ischemia and has been seen to essentially convert the period of warm ischemia into one representing ischemic preconditioning. An increasing number of reports have come out, primarily in the past two years, describing larger and larger series of transplantation of controlled DCD livers recovered with NRP. By and large, these series come from Europe and report rather low rates of biliary complications and in some cases, little to no ITVL, even using grafts from donors of advanced age and in some cases with extended donor warm ischemia. In Spain, the country in which I have the pleasure to live and work, controlled DCD was piloted in 2009 and formally regulated in 2012. At that time, the national protocol that was implemented created a unique situation in the country, allowing for either standard rapid preservation recovery or in-situ NRP to be used for abdominal organ recovery. In spite of initial increased use of standard rapid recovery relative to normothermic regional perfusion, improved results and experience with NRP and controlled DCD resulted in a nearly exponential rise of controlled DCD liver transplantation performed with NRP for every year since 2012. We have recently completed an analysis of all controlled DCD liver transplants performed between 2012 and 2019 in Spain, all with at least a year of follow-up, observing clearly superior graft survival for livers recovered with NRP. Focusing only on transplants performed with NRP, we identified subsets of grafts, namely those with a cold ischemia prolonged beyond seven hours and complex recipients, undergoing re-transplantation in particular with significantly worse outcomes, indicating that there might be an additional role for ex-situ preservation in these subsets of grafts. Another important utility of machine perfusion in marginal liver transplantation is using it to assess graft viability and to decide whether or not to proceed with transplantation. For adequate viability assessment, again, NRP needs to be performed. Following one small case series, two reports were published from centers in the UK, namely Cambridge and Birmingham, describing the transplantation of livers rejected by all UK centers after an ex-situ viability assessment. A relatively large proportion of the grafts were from DCD, some with extended donor warm ischemia times. Following what was determined to be a positive viability assessment, 22 grafts were transplanted in each experience, with good immediate graft function overall. ITBL rates remained relatively high, however, suggesting need for refinement of biliary viability criteria during ex-situ NRP. In this regard, the Groningen Group has reported on a promising alternative, whereby ischemically injured livers are initially reconditioned with dHOPE, followed by controlled re-warming, and finally NRP viability assessment. While one case of ITBL was still observed, the authors observed that the graft was one that did not actively alkalinize bile relative to the perfused, reinforcing the importance of assessing different aspects of graft function, including cholangiocellular as well as hepatocellular function, to determine true adequacy for transplantation. To conclude, while standard quality livers do not appear to benefit from perfusion preservation strategies, transplantation of marginal livers is improved with machine perfusion preservation. Steatotic livers suffer more with cold ischemia and can benefit from either continuous northermic machine perfusion or dHOPE, which target injured mitochondria. DCD livers should either be recovered with NRP or undergo dHOPE to reduce rates of ITBL, or even both strategies combined. Finally, livers of seriously questionable quality can only be transplanted after further assessment through XT2NRP, ideally after an initial period of dHOPE reconditioning. Thank you very much for your time and attention, and I welcome your questions at this time.

transplant metrics

liver transplant centers

organ acceptance rate

waitlist survival

graft survival

global focus

organ transplantation

supply-demand disparity

chronic kidney disease

patient outcomes

machine perfusion preservation

deceased donor liver transplantation

biliary complications

marginal quality liver grafts

post-transplant outcomes